Missing Links Between Genetically Inherited

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Original Article

Missing Links Between Genetically Inherited Molecules in Split Cord Malformation and Other Anomaly: A Bench to Bedside Approach Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 1Department of Anatomy, All India Institute of Medical Sciences (AIIMS), Bhubaneswar, Odisha, 2 Chief Neuroscience Centre and Dean Research, AIIMS, New Delhi, India

Abstract

Mayadhar Barik, Pravash R. Mishra1, Ashok Kumar Mohapatra2

Aim: Split cord malformation (SCM) is associated with extensive vertebral fusions (Klippel–Feil anomaly). In light of previous embryological theories and recent research findings, we attempt to document the origin of split cord, and vertebral fusions involvement of spectrum of genes is necessary to know better the etiopathogenesis of SCM and its associated diseases. Materials and Methods: We used the various databases such as PubMed/MEDLINE, Cochrane Review, Hinari, and Google Scholar for the recently published medical literature. The women had been living and still born infants had SCM. The relative risk (RR) and possible molecular mechanism are described details of major genes and its variants in details. Although molecular genetics involvement including with recent advances of study add an evidence of both Mendelian and Non-Mendelian fashion is discussed with all genetic components. We mentioned our earlier experience and responsibility of SCM and its associated diseases. Results: Although different mechanisms are suggested for the development of SCM observed in our experience, there is a midline lesion bisecting the neuroepithelium and the notochordal plate, which is responsible for complete splitting of the cervical cord with anterior bony defect. The localized disturbance of cervical neural tube closure accounts for SCM with partial dorsal splitting of the cord with posterior vertebral defect and associated diseases. Conclusions: According to the best of our knowledge, this report is the first one to be documented by wider spectrum of variants from (experimental studies to human subject). This add a complex interaction of mutant variants drive toward an additional second-hit alterations for the SCM. The up-to-date information, documented in proper order, derived the bench-to-bedside approach to overcome this burden of SCM, which is globally noticed with other additional diseases. Keywords: Genes, genetically inherited molecules, split cord malformation

Introduction

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urrently, higher cervical split spinal cords associated with extensive vertebral fusions (Klippel–Feil anomaly) are frequently found in the Indian population. Embryological theories and recent research findings suggest the origin of split cord malformation (SCM) and vertebral fusions.[1] Distinctly separate mechanisms suggested for the development of split cords have been observed in our patients.[2] Basically, midline lesion bisecting the neuroepithelium and the notochordal plate is responsible for complete Access this article online Quick Response Code:

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DOI: 10.4103/jpn.JPN_124_17

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splitting of cervical cord with anterior bony defect.[3] The cervical neural tube closure (CNTC) is responsible for partial dorsal splitting of the cord in cases with the posterior vertebral defect (PVD).[4] Vertebral fusion anomalies (VFAs) were associated with a disturbance Address for correspondence: Dr. Mayadhar Barik, TEJASWINI AWARDEE, Senior Scientific Advisor and Editor-in-Chief, Clin Diag (A Division of Monash International) New Delhi, India. E-mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected]

How to cite this article: Barik M, Mishra PR, Mohapatra AK. Missing links between genetically inherited molecules in split cord malformation and other anomaly: A bench to bedside approach. J Pediatr Neurosci 2018; 13:46-57.

© 2018 Journal of Pediatric Neurosciences | Published by Wolters Kluwer - Medknow

[Downloaded free from http://www.pediatricneurosciences.com on Thursday, May 17, 2018, IP: 14.139.245.2] Barik, et al.: Missing links between genetically inherited molecules in split cord malformation

Table 1: Major table of gene involvement on split cord malformations Sl. no Responsible gene 1. Pax-1

Chromosomal location 20p11.22

Mutagenicity/polymorphism Silent

2.

Grhl2

15; 15 B3.1

3. 4.

Grhl3 Grhl2 and Grhl3

1p36.11 15; 15 B3.11p36.11

5. 6.

SHH Zfh-1

7.

DeltaEF1

8. 9.

MTHFR MTRR

10.

MECP2

7q36.3 Drosophila zfh-1 gene encodes Heterogeneous DNA-binding domains 11p13 rs 1801394rs 1801133 5p15.31 Xq28

Novel downstream EMT suppressors Conserved Novel downstream EMT suppressors + conserved Point Loss of function

Duplication

11.

MECP2 and L1CAM

Xq28

Duplication

12.

ZRS

7q36.3

Limb bud mutation

13. 14. 15.

X-chromosome W237X 5p13.2–3 to 5pter

Deletion

16. 17.

Xq22.1 CLDN16 Ring chromosome (r(5) PAX2PAX6 HOX

18.

TUBAIA

10q24.3111p13 7p15, 17q21.2, 12q13, and 2q31 12q13.12

Null mutant

Disease-specific Vertebral fusion anomalies + split cord in the cervical region Split face malformation + exencephaly Spinal closure defect + DLHP Rostral and caudal neural tube defects CRS + SB Embryonic mesoderm and nervous system

5q deletion

Notochord, somites, neural crest, brain, spinal cord, and skeletal defects Complex congenital abnormalities Complex congenital abnormalities + multiple birth defects Neurodevelopmental disabilities + recurrent infection + hydrocephalous Mental retardation + hydrocephalous + corpus callosumBrain structural abnormalities Limb abnormalities, polydactyly, tibial hypoplasia, and syndactyly Congenital abnormalities Genetic defects + tubular disorders Multiple congenital abnormalities

Microdeletion Germ line

Development of optic disc anomalies Congenital abnormalities

MissenseAlternative splicing Alternative splicing

Heterozygous

Microphthalmia, congenital cataracts, microcephaly, and brain malformation 19. ATRXLICAM Xq21.1 Nonsense MPS + clinical phenotypes 20. USP9X Xp11.4 Alternate transcriptional splice MPS + clinical phenotypes + autism PAX1 = PAX1 paired box 1 (Homo sapiens [human]), Grhl2 = Grainyhead-like 2 (Drosophila) (Mus musculus [house mouse]), SHH = sonic hedgehog (Homo sapiens [human]), Zfh-1 = zinc finger motifs and one homeodomain, methyl-CpG binding protein 2, DeltaEF1-ZEB1 = zinc finger E-box binding homeobox 1, MTHFR = methylenetetrahydrofolate reductase, MTRR = 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, MECP2 = methyl-CpG binding protein 2, LICAM = Intracellular adhesion molecule-1 (Homo sapiens [human]), ZRS-LMBR1 = (ZRS) limb development membrane protein 1, CLDN16 = Claudin-16 (Homo sapiens [human]), PAX2 = paired box 2, HOX = a subset of homeotic genes, TUBAIA = TUBULIN, ALPHA, brain-specific-Alpha-1, ATRX = alpha thalassemia/mental retardation syndrome X-linked, USP9X = ubiquitin-specific peptidase 9 and X-linked

in PAX1 gene expression. As a developing vertebral column, frequent association of failure of normal segmentation and split cord in the cervical region (CR) located is quite informative.[5] Patients complained of neurological deficit (NLD) as mild and they had no radiological evidence of tethering.[6] The cord and spine and the rarity of a bony spur in the CR are the likely reasons of conservative policy.[7] Primary neurulation in mammals is defined as the distinct anatomical closure sites at the hind brain/cervical spine (closure 1), forebrain/midbrain boundary (closure 2), and rostral end of the forebrain (closure 3).[8] The zones of neurulation were characterized by the morphologic

differences in neural fold elevation, with nonneural ectoderm-induced formation of paired dorso lateral hinge points (DLHP) necessary for neural tube closure in both the cranial and the lower spinal cord regions.[9] The notochord-induced bending at the median hinge point is sufficient for the closure in the upper spinal region (USR).[10] The function of the nonneural ectoderm-specific Grainy head-like genes in human subject is important now.[11] Grhl2 gene-targeting approach is deletion of Grhl2, resulting in failed closure 3, mutants exhibiting a split face malformation, and exencephaly.[12] Failure of neuroepithelial folding

Journal of Pediatric Neurosciences ¦ Volume 13 ¦ Issue 1 ¦ January-March 2018

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Table 2: Specific gene involvement and neurulation site of split cord malformations (SCM) Sl. no 1. 2. 3. 4.

Responsible gene Chromosomal location Site Disease-specific Closure zone Grhl1 2p25.1 DLHP USR Closure1 Grhl2 15; 15 B3.1 MHP NNES Closure2 Grhl3 1p36.11 DLHP LSCD Closure3 Combine 15; 15 B3.1 DLHP RACNTD CNC Grhl2 1p36.11 Grhl3 DLHP = dorsolateral hinge points, MHP = median hinge points, USR = upper spinal region, NNES = nonneural ectoderm specific, LSCD = lower spinal closure defect, RACNTD = rostral and caudal neural tube defect, CNC = complete neuraxis closure

at the DLHP has loss of Grhl3 alone, which defined the distinct lower spinal closure defect.[13] DLHP formation genes contribute equally to closure 2, and only Grhl gene dosage is limiting. Deletion of Grhl2 and Grhl3 induces rostral and caudal neural tube defects.[14] DLHP-independent closure 1 proceeds in the USR. The DLPH findings on the basis of non neural ectoderm mediated by the formation of DLHP is critical for complete neuraxis closure (CNC).[15] Male infant of healthy non-consanguineous parents was born with congenital malformations (CMFs) is the one of challenges for the society,[16] which include bilateral cleft palate and lip, mild microphthalmia with iris coloboma and glaucoma of the right eye, and blepharophimosis with severe microphthalmia of the left eye as well [Table 2]. The spine radiograph, computed-tomography image and magnetic resonance imaging (MRI), showed first sacral hemivertebra with spina bifida (SB) and agenesis of the 2nd, 3rd, 4th, and 5th sacral vertebrae and coccyx. The spine MRI showed caudal tethering of spinal cord at L(3) level, filum terminalis lipoma, and syringomyelia.[17] Anophthalmia-plus syndrome (APS) had a distinct syndrome having gene locus of APS research is now in progress with this new subjects.[18] Human development series of first-trimester abortions were studied in the embryo with expression of sonic hedgehog (SHH) was found in both domains SCM.[19] SCM corresponding with duplicated part of the notochord, single signal observed that no duplicated part located on development.[15] The cervical level of the open neural tube with SHH expression domain and with two or even three domains in its lumbar region is quite important.[20] Multiple functional floor plates (MFFPs) along with two embryos leads SB. SHH expression found in the ventral neural tube (VNT) frequently.[21] Static magnetic fields involved in the pathogenesis of CR and similar notochord abnormality and altered expression of the SHH gene observed in Lp mice with neural tube defect (NTD).[20] Lp gene is a candidate gene (CG) for human CR.[15] The notochord splitting and for the 48

abnormal expression of the SHH gene in the floor plate in embryos with CRS and SB questionable.[22] DeltaEF1 is a DNA-binding protein containing a home domain and two zinc finger clusters. Located in vertebrate homologue of zfh-1 (zinc finger homeodomain-containing factor-1) in Drosophila species.[23] DeltaEF1 is expressed in the notochord, somites, limb, neural crest derivatives (NCD), and few restricted sites of the brain and spinal cord.[24] Regulatory function of deltaEF1 helps in embryogenesis. DeltaEF1 has a role in regulating the development of skeletal structures.[25] DeltaEF1, deltaC727, and deltaEF1 having various regulatory activities (VRA) are dependent on different domains.[26,27]

Materials and Methods We used different databases PubMed/MEDLINE, Cochrane Review, Hinari, Google Scholar for recent medical literature. The women who had live-and stillborn infants, of whom had SCMs are also in relative risk of SCMs. The possible molecular mechanisms we were described details in the table major genes and its variants through molecular genetics involvement clearly. This including with recent advances and future prospective. It add an evidence of both Mendelian and Non-Mendelian fashion. We are trying to document and summarize all responsible possible genes and recent advances approach with bench to bedside approach.

Results The association of polymorphisms in folate metabolism genes (FMG), methionine synthase reductase (MTRR) gene, and 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene, with complex congenital abnormalities (CCA) and its association with CCA are derived from three germ layers.[28] MTRR single nucleotide polymorphisms (SNPs) (rs1801394) and MTHFR SNP (rs1801133) are genotyped with multiple birth defects.[29] The homozygous recessive genotype (HRG) at rs1801133 served as a protective factor (PF).[30] Ectoderm- or endoderm-derived CCA are HRG (rs1801394) and served as a PF.[31,32] SNPs in



FMG (MTRR and MTHFR) associated with CCA and related to ectoderm, mesoderm, or endoderm development significantly.[33] Chromothripsis is an extreme class of complex chromosomal rearrangements (CCR) with major work on chromosomal architecture (CA).[34] Chromothripsis with congenital abnormalities (CCA) has incidence of pathogenic effects.[35] Human genome tolerates extreme reshuffling of CA.[36] Basically, in breakage point of multiple protein-coding genes (MPCGs) had a nature without noticeable phenotypic effects.[37] Chromothripsis in healthy individuals affects reproduction and increases the risk of miscarriages, abortions, severe congenital disease, and direct involvement with birth defects.[38] MECP2 duplication is a well-recognized syndrome in 100% of the affected male children with neurodevelopmental disabilities and recurrent infections.[39] MECP2 and L1CAM genes in the Xq28 region in family with severe X-linked mental retardation (MR) are higher.[40] Prenatal fetus with the brain structural abnormalities is identified from the fetuses with MECP2 duplication.[39] Hydrocephalus, agenesis of the corpus callosum, choroid plexus cysts, fetal growth restriction, and hydronephrosis might be the common ultrasound findings in prenatal fetuses with MECP2 duplication, which is now more challengeable and newly recognized.[41] In ZRS, a highly conserved cis-regulator, long-range gene regulation is noticed.[42] It acts over approximately 1 Mb to control spatiotemporal expression of SHH in the limb bud.[43] ZRS mutations promote limb abnormalities, including polydactyly, tibial hypoplasia, and syndactyly.[44] Prenatal diagnosis (PD) found a duplication on the long arm of chromosome X from chromosomal band Xq13.2 to q21.31 in a male fetus with increased nuchal translucency in the first trimester and polyhydramnios at 22 weeks of gestation period.[45] The amniocentesis with cytogenetic analysis (CA) revealed chromosomal material (CM) in the long arm of chromosome X at position Xq13.[46] Analysis with higher resolution array CGH revealed the additional material is in fact a duplication of the region Xq13.2-q21.13.[47] Duplication is 14.8 Mb in size and includes the following genes: SLC16A2, KIAA2022, ABCB7, ZDHHC15, ATRX, MAGT1, ATP7A, PGK1, TBX22, BRWD3, POU3F4, ZNF711, POF1B, and CHM.[48] In according to analysis of the parents revealed that mother to be the carrier of the same duplication also a causal factor of SCM. After elective termination of the pregnancy at 28 weeks, a detailed autopsy of the fetus allowing genotype-phenotype correlations is required for necessary investigations.[49]

Multiple congenital abnormalities (MCAs) are caused by the chromosomal aberrations, mutant major genes and teratogens.[48] Patients are identified as with syndromes but the major part belonged to the group of unclassified multiple CAs (UMCAs).[50] Young-aged mothers are associated with the higher risk of UMCA.[51] Birth order 4 or more is associated with the higher risk for UMCA with 2 and 3 component CAs.[52] The possible maternal and birth order effect for cases with UMCA, and the young age and higher birth order associated with a higher risk for UMCA were analyzed.[50] Chromosomal microarray analysis (CMA) identified a novel 1.1-Mb deletion at Xq22.1. A similar deletion has been described once in the literature.[47] Female patient and her mother both have intellectual disability (ID) and dysmorphic facial features of a 0.35-Mb subregion[53] containing four genes, which is sufficient to cause majority of the Xq22.1 deletion phenotypes. Male and female patients contain 30 common genes, including the 4 described in the 0.35-Mb subregion.[54] Male with deletion of the 0.35 Mb subregion died prenatally from respiratory failure due to pulmonary hyperplasia, consistent with the breathing problem and potential neonatal fatality in male patients.[55] The patients were strikingly affected with similar fashion. The deletion of these five genes (ARMCX5, ARMCX5-GPRASP2, GPRASP1, GPRASP2, and BHLHB9) is likely responsible for the novel Xq22.1 deletion syndrome.[56] Congenital anorectal malformation (ARM) is one of the most common gastrointestinal congenital diseases accounting for one-fourth of digestive tract malformations[57] and is one of the CMFs in routine surveillance by the World Health Organization.[58] Of the variety of risk factors and the complexity of the pathological changes, etiology of ARM is a unique one.[49] ARM results from hereditary factors and environmental factors in the development of embryogenesis.[59] Through all the animal experiments, we have observed that HOX, SHH, FGF, WNT, Cdx, and TCF4, Eph, and ephrin play a crucial role during the development of digestive tract because of the genes/signaling pathway dysfunction.[60] ARM is the external factor in pregnancy.[61] Because of this complexity in SCM and related factors are responsible in the development process of human embryogenesis,[62] research on the progress of human ARM is still going on. Reviewing in appropriate genetic and environmental factors we provide the theoretical/practical basis for the treatment and prevention of ARM is quite necessary.[63] Fetal lung interstitial tumor (FLIT) is a


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newly recognized lung lesion in infants.[64] Histological examination revealed immature airspaces and interstitium, containing bronchioles and cartilage.[65] The epithelial and interstitial cells (EIC) contained abundant glycogen granules. Immunohistochemistry (IHC) showed nuclear/cytoplasmic expression of β-catenin in the EIC, report are very interesting to know the disease progression and aetiopathogenesis.[66] β-Catenin gene mutations and trisomy 8 are neoplastic origin could not be confirmed till date.[67] Histological findings (H and E) were partly consistent with normal fetal lung at the canalicular stage, pulmonary interstitial glycogenesis, and congenital cystic adenomatoid malformation/congenital pulmonary airway malformation (CPAM) type 3.[68] However, we compare the above conditions and discuss the pathogenesis of FLIT.[69] Familial hypomagnesemia (FH) with hypercalciuria and nephrocalcinosis is an autosomal-recessive renal tubular disorder.[70] It is characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis, and progressive renal failure with mutations.[71] Paracellin-1 (CLDN16) gene been defined as the underlying genetic defect frequently.[72] Tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy.[73] Hypomagnesemia improves with advanced renal insufficiency. A patient was presented with a homozygous truncating CLDN16 gene mutation (W237X)[74] who had an early onset of renal insufficiency despite early diagnosis at 2 months. The patient also had horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia, and hypertrichosis.[75] FH with hypercalciuria and nephrocalcinosis and additional congenital abnormalities (ACAs) were independent of the disease.[76] A child with a ring chromosome 5 (r(5)) associated with facial dysmorphology and MCAs was noticed by researchers.[72] Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome clones was performed to determine the breakpoints involved in the r(5).[77] The 5p deletion extended from 5p13.2-3 to 5pter and measured 34.61 Mb (range, 33.7–35.52 Mb), whereas the 5q deletion extended from 5q35.3 to 5qter and measured 2.44 Mb (range, 2.31–2.57 Mb).[78] The patient presented with signs such as microcephaly, hypertelorism, micrognathia, and epicanthal folds, partially recalling deletion of the short arm of chromosome 5 and the “Cri-du-chat” syndrome.[79] The phenotypic features such as the

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congenital abnormalities (CAs) were frequently reported.[80] Deletions of the distal part of the long arm of chromosome 5 and in rings lead to a 5q35-5qter deletion.[81] NKX2-5 gene had been related to congenital heart defects (CHDs), patients including with 5q35.3-5qter deletion is important cause for SCM.[82] Additionally, VEGFR3, deleted in patient, a CG for the congenital heart abnormalities (CHAs) were observed with SCM and also associated diseases.[78]

Discussion Recently, MSX1 gene, which helps in outflow tract morphogenesis, was found in a fetus with isolated heart (IH) in hypermethylation of the GATA4 gene. Fetuses with Down syndrome with or without CHDs are newly recognized. In fetuses with IH malformations, epigenetic alterations of relevant genes are present in developing heart DNA. In fetuses with both isolated and syndrome heart malformations, pathogenesis is related to the malformation by cis-acting effects and gene expression.[83] Optic nerve malformations are common causes of congenital blindness and are recognized with increasing prevalence. These malformations help not only in determining the cause and level of visual impairment but also in looking for associated treatable or life-threatening systemic conditions such as PAX2 or PAX6 gene. Recent advances in genetic testing such as array technology distinguished the comparative genomic hybridization and allow to detect the micro deletions.[84] PAX2 provides the clue for further research and avoids publication bias.[85] Congenital anomalies in the kidney and urinary tract (CAKUT) are common genetic malformations. PAX2 gene has a role in kidney organogenesis and antenatal hydronephrosis in healthy controls. In genotyping and allelic discrimination find out by probes were rs2077642, rs4244341, rs6421335, rs11190698, and rs11190693. PAX2 gene involved with the pathogenesis of Vesicoureteral Reflux (VUR) in children subject is one important information.[86] Defects in these processes are the common causes of CMF syndromes, and rapid progress is being made in elucidating their embryological and genetic basis. Perturbation in the DiGeorge syndrome is the second induction at differentiation of the forebrain. Holoprosencephaly the third role played by the human HOX genes in CMFs.[87] TUBA1A mutation is responsible to creating microphthalmia.[88] Congenital nephrotic syndrome (CNS) is a rare disease inherited as an autosomally recessive trait and defined as proteinuria manifesting at birth or in the first 3 months of life. The classical form is the Finnish type is one classical example of SCM.



The classical findings included prematurity, large placenta, and massive proteinuria. Minor cardiac findings have been reported as a minor functional disorder, but CNS with major cardiac malformation is rare. Child with CNS with small indel mutation (c.614_621delCACCCCGGinsTT) in exon 6 of NPHS1 had major role in cardiac malformation and developed end-stage renal disease (ESRD).[89] Patients with occlusive vascular Ehlers–Danlos syndrome accompanying a congenital cystic adenomatoid malformation of lung, in addition to duplicated infrarenal vena cava, have been reported.[90] Type 2 CPAM is reported in association with other congenital anomalies. Type 2 CPAM with CNS has not been reported. First report of such an association in a boy had a PD of cystic lung malformation and was found to have CNS (diffuse mesangial sclerosis) at 1 month of age.[91] CAKUT was seen in approximately 45% of the children with ESRD in Indian population. Mutations in 30 genes were described as causing autosomal-dominant isolated CAKUT in human subjects.[92] The degree of an intrauterine fetal growth retardation (IUFGR) is depends on number of component CA in UMCA cases were newly Observed by the researchers.[50] Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan and varies in the Indian scenario. Sudden death occurred in MNK patients with CM conditions.[93] Developmental delay (DD) and/or ID affects 1%–3% of children. Causative variants are identified in patients who had a nonsense mutation. ATRX gene and a canonical splice site mutation in the L1CAM gene with splice site variant in the USP9X gene help clinical phenotypes. Gene MPS is likely to provide a genetic diagnosis for children with autism phenotype.[94] As a typical presentation of anterior meningocele in a young adult with urinary incontinence, a sacral defect, ARM and headaches during bicycle riding also a great example in rare cases.[95] Heart- and NCD-expressed (Hand) proteins are the Twist family of the basic helix-loop-helix (bHLH) transcription factors. TWIST plays crucial role in the development. Hand2 results in developmental defects of limbs, craniofacial, and lumbar vertebrae, and trisomy of the Hand2 gene is involved with human congenital disorder.[96] Polymorphisms of OSR1 gene rs12329305, rs9936833 near FOXF1, and HOXA1 rs10951154 polymorphism in the development of CMFs stillborn/ neonatal death occurred with congenital kidney (CK) and heart developmental defects (HDDs) were still a challenging task.[97]

Periconceptional folate supplementation prevents a number of congenital anomalies (CA). MTHFR C677T and MTR A2756G loci were increased the risk of CA-affected pregnancy. MTHFR A1298C and its associated of MTR A2756G increased the risk of CA. Locus A2756G in MTHFRR gene susceptibility also counted as an important information for the SCM.[98] CMF of external and middle ear is a common disease in the ENT department. External and middle ear malformations an important ear symptom of the systemic syndrome confirmed with genetic research progress of CMF of external and middle ear.[99] Identical twins with lethal CPAM type 0 an autosomal-recessive inheritance pattern responsible in familial recurrence (FR).[100] Congenital cardiovascular malformation (CCVM) exhibits familial predisposition, the specific genetic factors involvement are unknown. Genes of the bone morphogenetic protein (BMP) signaling pathway for novel variants are exonic, splice site, and untranslated regions of BMPR1A, BMPR2, and SMAD6 genes. Researchers believe that low-frequency deleterious variants in SMAD6 predispose into CVM human disease phenotype genetic variation with SMAD6 is one of the new message for student.[101] P63-positive cells are epithelium of the apical urorectal septum (AUS), hindgut, and cloacal membrane. Mutation identified that P63 strongly causal factors among the ARM phenotype and P63. P63 helps in incessant septation of the cloaca and hindgut in the morphogenesis.[102] Apert, Fibroblast Growth Factor (FG), Floating–Harbor, Shprintzen–Goldberg, and Rett syndromes and craniosynostosis diseases are developed through the MECP2 gene mutation globally.[103,104] CCR, is important for balanced or unbalanced structural rearrangements, are cytogenetic break points on CMA.[105] Submicroscopic deletions at 3p12.3 (467 kb) and 12q13.12 (442 kb) are having important role for CMA.[106] Microdeletion within ROBO1 gene at 3p12.3 played a role in the patient’s DD, potential activity-dependent role in neurons, and IQ.[107] Neural elements are proper interaction with the brain. So, congenital spinal deformities had normal embryologic development.[108] Hmx1 expression in neural-crest-derived CM and deregulation of Hmx1 expression acted candidate mechanism for congenital ear malformation. Split hand/split foot malformation (SHFM) type 1 missing central digital rays with clefts of the hands and/or feet, which was linked to chromosome 7q21.3. Dlx5 and Dlx6 help limb defects in human subject.[109] SHFM1 caused heterozygous paternal deletion, enhancers the osteoblast-specific maternally imprinted through these (DLX6 and DLX5 genes).[110]


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HUB genes were identified that (UBC, APP, HUWE1 and SRC) are potential biomarkers for CHD in DS.[111] Novel mutations, c.559C>G (p.P178A) and c.682T>A (p.C228S), in the SYM1 and atypical SYNS1 families changes found in the protein-coding regions, exon-intron boundaries or promoter regions. The NOG, GDF5 or FGF9 genes were found in the SABTT family. These syndromes are help in the diagnostic purpose for “NOG-related-symphalangism spectrum disorder”.[112] Microtia is a complicated congenital anomaly had a genetic and environmental predisposition. miR-200c expression of miR-451 and miR-486-5p expression in microtic causes abnormal development of the external ear. OSR1 and TRPS1 genes were complementary target of mRNAs had an important role during the development.[113] FOXI3 gene responsible for patient with SCM and its associated diseases for new information for further study.[114] Congenital vertebral malformation (CVM) is a congenital vertebral structural deformity caused by abnormal somitogenesis during embryonic development. Copy number Variations (CNV) of chromosome 16p11.2, 10q24.31, 17p11.2, 20p11, 22q11.2 like few other regions is associated with CVM. This gene dosage plays an important role in the development of the spinal cord and SCM.[115] 1p36 deletion (monosomy 1p36) is a common terminal deletion observed in human subjects. Patients with limb, CHDs, and other malformations with SNP array report proved they having small deletion. Aditionally, 1p36.33-p36.32 had SKI (Sloan–Kettering Institute proto-oncoprotein) also one causal factor for CHDs. Dominant mutations in SKI identified are with Shprintzen–Goldberg syndrome. 1p36.33-1p36.32 deletion encompassing SKI represents a previous undescribed microdeletion disorder.[116] Presently, ITI (inter-trypsin inhibitor) gene family consisting of five genes (ITIH1 to ITIH5) encodes proteins involved in the dynamics in the extracellular matrix. ITIH5 found inactivated by partial deletion in a case of congenital uterovaginal aplasia among human subject rare diseases are called Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.[117] Female reproductive tract and ITIH5 considered as putative CG for MRKH syndrome. MR and MCAs are associated with microdeletion/duplication syndromes noticed by the earlier researchers.[118] Persistent hyperplastic primary vitreous (PHPV) is identically same as persistent fetal vasculature, rare congenital developmental malformation of the eye, and failure of regression of the primary vitreous. Norrie disease with FZD4 genes is found to be mutated 52

in unilateral and bilateral PHPV. Potential CGs are the future and provide a better understanding of the pathogenesis, therapeutic approach, and better management for SCM.[119] CMFs in the female population are estimated to be 5:1000 live births associated with infertility, abortion, stillbirth, preterm delivery, and other organ abnormalities. The homeobox (HOX) genes (HOXA10 and HOXA13) are involved in the development of human genitalia. HOXA10 gene helps in misdevelopment of female internal genitalia, which should not be ignored.[120] Mitogen-activated protein kinase (MAPK) pathway and genes (FGF18, FGF12, PDGFRA, MAPK11, AMH, and CTBP1) are involved in organ development and morphogenesis. Genome level shown that no genetic factors also involved in pathogenesis of renal agenesis.[121] SHFM had variable degree of median clefts on hands and feet. Genes (TP63, WNT10B, and DLX5) are promoting SHFM phenotype with involvement of hands and feet. Genotyping using microsatellite markers to map the families to WNT10B gene at SHFM6 on chromosome 12q13.11-q13 is newly discussed.[122] Sequence analysis of WNT10B gene revealed a novel 4-bp deletion mutation (c.1165_1168delAAGT) and 7-bp duplication (c.300_306dupAGGGCGG). Structure-based analysis showed conformational shift within active binding site mutated by WNT10B (p.Lys388Glufs*36). It influences in binding with FZD4. The WNT10B gene extends the body of evidence and helps in the pathogenesis of SHFM.[123] Congenital hypothyroidism (CHT) and mutations in genes involved in thyroid development, patients according to their CH-T etiology, types, and patterns in morphological findings helpful in how thyroid development.[124] Karyotype is found patients chromosomal rearrangement, different break points the identified genes (NRCAM, NPTX1, NMT1, MAPT, HDAC5 and MEF2C) associated with SCM and its associated diseases (due to a position effect).[125] SHFM along with -bone deficiency is the rarest condition in SHFM. Which associated with long-bone malformation (LBM) involved with the tibia. SHFM had located on 17p13.3 duplication and BHLHA9 copy number gains similarly associated with limb defect presenting ectrodactyly and harboring a BHLHA9 duplication is one important information mentioned in Table 1.[126] DNA sequence analysis provides the fundamentals of gene study of the congenital craniofacial abnormalities. Human genome project paved the confirmation of CG of the congenital craniofacial abnormalities and enlighten to know the association of SCM with its associated diseases.[127]



Future Prospective and Recommendations The first success in cloning sheep, the production of viable animals somatic cell nuclear transfer (SCNT) developed is now time to remember and analyze. The most successfully cloned cattle species. Newer techniques are still associated with a higher incidence of pregnancy failure and accompanying by the placental and fetal pathologies. Pre- and early postimplantation losses affected up to 75% of the pregnancies. The SCNT placenta appears normal, placental vascularization modified and fetal-to-maternal tissue ratios are slightly increased in the SCNT placentomes.[128] Gsc gene and BMP5 gene mutation both environmental and genetic factors contribute to congenital microtia. So that Gsc gene and BMP5 maternal peptide gene predisposing genes of microtia.[129] Molecular genetics study in molecular level, genetic information is stored, inherited, expressed, and influenced by the structure and function of cells in SCM and its associated diseases progression is more important. Several molecular approaches been used for decades in the laboratory and core of modern medical education are only now beginning to influence clinical practice and research. Newer techniques permit rapid and affordable DNA sequencing, gene expression profiling, gene cloning, gene manipulation, gene transfer, recombinant protein production, gene editing, and other technologies of enormous biomedical importance for SCM and associated diseases. As a genomics era grown up including proteomics, pharmacogenomics, and bioinformatics. Recently newer techniques are providing diagnostic, prognostic, and therapeutic opportunities in all areas of medicine and promote translational research. Presently, somatic and germ line variants in genes at the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) associated with MCAP and/or other related megalencephaly syndromes. Clinical features are macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, DD, discrete midline facial nevus flammeus, toe syndactyly, and postaxial polydactyly—thus, clearly an MCAP phenotype are very clear cut message for recent young researchers. Nowadays, an exome-based sequencing helps pathogenic de novo germ line variants [PTPN11 gene (c.1529A>G; p.(Gln510Arg)]. a PTPN11], germ line variant in MCAP patient had major impact. The new data from experimental studies have shown the complex interaction of SHP2 (gene product of PTPN11) within PI3K-AKT pathway. PTPN11 germ line variants drive toward an additional second-hit alterations for SCM and its associated diseases are very unique information for researchers and neurosurgeon as well.

Split cord malformation treatment in India

In the 2-year period, 2008–2009, a total of 53 cases with SCM, an uncommon condition, were examined. With all cases of progressive scoliosis, an MRI was carried out. All asymptomatic patients were subjected to surgery and none developed post-op deterioration. The post-op neurological deterioration (ND) was noticed in 15% patients, of which 8% had transient postoperative deterioration. The new type I SCM subclassification system proposed by Borkar and Mahapatra is found to have a significant prognostic value in assessing postoperative ND in patients with type I SCM.[130] With decreasing incidence of NTD in the West, the reports of SCM are getting lesser and lesser. However, in India, spinal dysraphism is still a major problem encountered by the neurosurgeons. SCM is rare and not many large series are available in literature. We operated 300 cases and noticed a large number of associated anomalies with multilevel and multisite splits. Improvement or stabilization was noted in 94% and deterioration in 6% of the cases, and prophylactic surgery for asymptomatic patients was recommended.[131] Again complete neural axis scan is the first instance to determine associated lesions. Very good results were expected in about 90% patients, with minimal complications documented in 48 cases.[132] Incidence of SCM with Meningomyelocele (MMC) amounts to 41% of total SCM cases. Progressive NLD was higher among these groups (SCM with MMC) in comparison to the group harboring SCM without MMC. In view of a significant association of SCM in MMC cases, associated with other craniospinal anomalies, a thorough screening of neuraxis (by MRI) is recommended to treat all treatable anomalies simultaneously for desired outcome.[133] In a retrospective analysis study consisting of 19 cases with SCM, 13 were grouped under (Pang) type I and 6 under type II, including the age range from 1 month to 9 years (mean, 3.5 years). Kumar et al.[134] observed that surgery seemed to be effective, particularly in patients with neurological dysfunction (NLDF). Venkataramana[135] recommended that surgery before the onset of NLDs is quite important and surgical results are excellent with good microsurgical technique is helpful for the patients.

Conclusion In conclusion, not only genes but also many signaling, pathways, proteins, and enzymes are responsible for SCM and its associated diseases. In our experience, next-generation sequencing and genome-wide association study may help and support to know the better etiopathogenesis, future management, and may


53


help improve further development research for SCM and its associated diseases.

Limitation More samples are required and a strong database with appropriate tools is mandatory. Financial support and sponsorship

Nil. Conflict of interest

There are no conflicts of interest.

References 1. David KM, Copp AJ, Stevens JM, Hayward RD, Crockard HA. Split cervical spinal cord with Klippel-Feil syndrome: Seven cases. Brain 1996;119:1859-72. 2. Emura T, Asashima M, Furue M, Hashizume K. Experimental split cord malformations. Pediatr Neurosurg 2002;36:229-35. 3. Prasad VS, Reddy DR, Murty JM. Cervico-thoracic neurenteric cyst: Clinicoradiological correlation with embryogenesis. Childs Nerv Syst 1996;12:48-51. 4. Steinbok P. Dysraphic lesions of the cervical spinal cord. Neurosurg Clin N Am 1995;6:367-76. 5. Deutsch U, Dressler GR, Gruss P. Pax 1, a member of a paired box homologous murine gene family, is expressed in segmented structures during development. Cell 1988;53:617-25. 6. Missonnier P, Deiber MP, Gold G, Herrmann FR, Millet P, Michon A, et al. Working memory load-related electroencephalographic parameters can differentiate progressive from stable mild cognitive impairment. Neuroscience 2007;150:346-56. 7. Bams-Mengerink AM, Majoie CB, Duran M, Wanders RJ, Van Hove J, Scheurer CD, et al. MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata. Neurology 2006;66:798-803; discussion 789. 8. Rifat Y, Parekh V, Wilanowski T, Hislop NR, Auden A, Ting SB, et al. Regional neural tube closure defined by the Grainyhead-like transcription factors. Dev Biol 2010;345:237-45. 9. Copp AJ, Brook FA. Does lumbosacral spina bifida arise by failure of neural folding or by defective canalisation? J Med Genet 1989;26:160-6. 10. McShane SG, Molè MA, Savery D, Greene ND, Tam PP, Copp AJ. Cellular basis of neuroepithelial bending during mouse spinal neural tube closure. Dev Biol 2015;404:113-24. 11. Chalmers AD, Lachani K, Shin Y, Sherwood V, Cho KW, Papalopulu N. Grainyhead-like 3, a transcription factor identified in a microarray screen, promotes the specification of the superficial layer of the embryonic epidermis. Mech Dev 2006;123:702-18. 12. Auden A, Caddy J, Wilanowski T, Ting SB, Cunningham JM, Jane SM. Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development. Gene Expr Patterns 2006;6:964-70. 13. Joó JG. Recent perspectives on the genetic background of neural tube defects with special regard to iniencephaly. Expert Rev Mol Diagn 2009;9:281-93. 14. Harris MJ, Juriloff DM. Mini-review: Toward understanding mechanisms of genetic neural tube defects in mice. Teratology 1999;60:292-305. 15. Kirillova I, Novikova I, Augé J, Audollent S, Esnault D, Encha-Razavi F, et al. Expression of the sonic hedgehog gene in human embryos with neural tube defects. Teratology 2000;61:347-54.

54

16. Gulati R, Verdin H, Halanaik D, Bhat BV, De Baere E. Co-occurrence of congenital hydronephrosis and FOXL2-associated blepharophimosis, ptosis, epicanthus inversus syndrome (BPES). Eur J Med Genet 2014;57:576-8. 17. Makhoul IR, Soudack M, Kochavi O, Guilburd JN, Maimon S, Gershoni-Baruch R. Anophthalmia-plus syndrome: A clinical report and review of the literature. Am J Med Genet A 2007; 143A:64-8. 18. Panman L, Galli A, Lagarde N, Michos O, Soete G, Zuniga A, et al. Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling. Development 2006;133:3419-28. 19. Anderson E, Devenney PS, Hill RE, Lettice LA. Mapping the Shh long-range regulatory domain. Development 2014;141:3934-43. 20. Wilson L, Maden M. The mechanisms of dorsoventral patterning in the vertebrate neural tube. Dev Biol 2005;282:1-13. 21. Maden M. Retinoids and spinal cord development. J Neurobiol 2006;66:726-38. 22. Müller F, Albert S, Blader P, Fischer N, Hallonet M, Strähle U. Direct action of the nodal-related signal cyclops in induction of sonic hedgehog in the ventral midline of the CNS. Development 2000;127:3889-97. 23. Takagi T, Moribe H, Kondoh H, Higashi Y. DeltaEF1, a zinc finger and homeodomain transcription factor, is required for skeleton patterning in multiple lineages. Development 1998;125:21-31. 24. Mo R, Freer AM, Zinyk DL, Crackower MA, Michaud J, Heng HH, et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 1997;124:113-23. 25. Darling DS, Stearman RP, Qi Y, Qiu MS, Feller JP. Expression of Zfhep/deltaEF1 protein in palate, neural progenitors, and differentiated neurons. Gene Expr Patterns 2003;3:709-17. 26. Akiyama K, Katayama K, Tsuji T, Kunieda T. Characterization of the skeletal fusion with sterility (sks) mouse showing axial skeleton abnormalities caused by defects of embryonic skeletal development. Exp Anim 2014;63:11-9. 27. Lai ZC, Fortini ME, Rubin GM. The embryonic expression patterns of zfh-1 and zfh-2, two Drosophila genes encoding novel zinc-finger homeodomain proteins. Mech Dev 1991;34:123-34. 28. Lai ZC, Rushton E, Bate M, Rubin GM. Loss of function of the Drosophila zfh-1 gene results in abnormal development of mesodermally derived tissues. Proc Natl Acad Sci U S A 1993;90:4122-6. 29. Zhang Q, Bai BL, Liu XZ, Miao CY, Li HL. [Association of folate metabolism genes MTRR and MTHFR with complex congenital abnormalities among Chinese population in Shanxi Province, China]. Zhongguo Dang Dai Er Ke Za Zhi 2014;16:840-5. 30. Zhang Q, Bai B, Liu X, Miao C, Li H. Association of folate metabolism genes MTHFR and MTRR with multiple complex congenital malformation risk in Chinese population of Shanxi. Transl Pediatr 2014;3:259-67. 31. Pangilinan F, Molloy AM, Mills JL, Troendle JF, Parle-McDermott A, Signore C, et al. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects. BMC Med Genet 2012;13:62. 32. Liu J, Qi J, Yu X, Zhu J, Zhang L, Ning Q, et al. Investigations of single nucleotide polymorphisms in folate pathway genes in Chinese families with neural tube defects. J Neurol Sci 2014;337: 61-6. 33. Shaw GM, Lu W, Zhu H, Yang W, Briggs FB, Carmichael SL, et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. BMC Med Genet 2009;10:49.



34. de Pagter MS, van Roosmalen MJ, Baas AF, Renkens I, Duran KJ, van Binsbergen E, et al. Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am J Hum Genet 2015;96:651-6. 35. Kloosterman WP, Cuppen E. Chromothripsis in congenital disorders and cancer: Similarities and differences. Curr Opin Cell Biol 2013;25:341-8. 36. Pellestor F. Chromothripsis: How does such a catastrophic event impact human reproduction? Hum Reprod 2014;29:388-93. 37. Webb A, Papp AC, Curtis A, Newman LC, Pietrzak M, Seweryn M, et al. RNA sequencing of transcriptomes in human brain regions: Protein-coding and non-coding RNAs, isoforms and alleles. BMC Genomics 2015;16:990. 38. Fontana P, Genesio R, Casertano A, Cappuccio G, Mormile A, Nitsch L, et al. Loeys-Dietz syndrome type 4, caused by chromothripsis, involving the TGFB2 gene. Gene 2014;538:69-73. 39. Fu F, Liu HL, Li R, Han J, Yang X, Min P, et al. Prenatal diagnosis of foetuses with congenital abnormalities and duplication of the MECP2 region. Gene 2014;546:222-5. 40. Fukushi D, Yamada K, Nomura N, Naiki M, Kimura R, Yamada Y, et al. Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2. Am J Med Genet A 2014;164A:924-33. 41. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 2005;77:442-53. 42. Hill RE, Lettice LA. Alterations to the remote control of Shh gene expression cause congenital abnormalities. Philos Trans R Soc Lond B Biol Sci 2013;368:20120357. 43. Masuya H, Sezutsu H, Sakuraba Y, Sagai T, Hosoya M, Kaneda H, et al. A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud. Genomics 2007;89:207-14. 44. Wieczorek D, Pawlik B, Li Y, Akarsu NA, Caliebe A, May KJ, et al. A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Hum Mutat 2010;31:81-9. 45. Sismani C, Donoghue J, Alexandrou A, Karkaletsi M, Christopoulou S, Konstantinidou AE, et al. A prenatally ascertained, maternally inherited 14.8 Mb duplication of chromosomal bands Xq13.2-q21.31 associated with multiple congenital abnormalities in a male fetus. Gene 2013;530:138-42. 46. Sanlaville D, Schluth-Bolard C, Turleau C. Distal Xq duplication and functional Xq disomy. Orphanet J Rare Dis 2009;4:4. 47. Cao Y, Aypar U. A novel Xq22.1 deletion in a male with multiple congenital abnormalities and respiratory failure. Eur J Med Genet 2016;59:274-7. 48. Csermely G, Czeizel AE, Veszprémi B. Distribution of maternal age and birth order groups in cases with unclassified multiple congenital abnormalities according to the number of component abnormalities: A national population-based case-control study. Birth Defects Res A Clin Mol Teratol 2015;103:67-75. 49. Zhang Y, Ren H. [Research progress in genetic abnormalities and etiological factors of congenital anorectal malformation]. Zhonghua Wei Chang Wai Ke Za Zhi 2016;19:113-7. 50. Puhó EH, Czeizel AE, Acs N, Bánhidy F. Birth outcomes of cases with unclassified multiple congenital abnormalities and pregnancy complications in their mothers depending on the number of component defects. Population-based case-control study. Congenit Anom (Kyoto) 2008;48:126-36.

51. Csermely G, Susánszky É, Czeizel AE. Association of young and advanced age of pregnant women with the risk of isolated congenital abnormalities in Hungary - a population-based case-matched control study. J Matern Fetal Neonatal Med 2015;28:436-42. 52. Csermely G, Susánszky É, Czeizel AE, Veszprémi B. Possible association of first and high birth order of pregnant women with the risk of isolated congenital abnormalities in Hungary - a populationbased case-matched control study. Eur J Obstet Gynecol Reprod Biol 2014;179:181-6. 53. Zhou J, Goldberg EM, Leu NA, Zhou L, Coulter DA, Wang PJ. Respiratory failure, cleft palate and epilepsy in the mouse model of human Xq22.1 deletion syndrome. Hum Mol Genet 2014;23:3823-9. 54. Gazou A, Riess A, Grasshoff U, Schäferhoff K, Bonin M, Jauch A, et al. Xq22.3-q23 deletion including ACSL4 in a patient with intellectual disability. Am J Med Genet A 2013;161A:860-4. 55. Labonne JD, Graves TD, Shen Y, Jones JR, Kong IK, Layman LC, et al. A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies. BMC Neurol 2016;16:132. 56. Garcia-Miñaur S, Ramsay J, Grace E, Minns RA, Myles LM, FitzPatrick DR. Interstitial deletion of the long arm of chromosome 5 in a boy with multiple congenital anomalies and mental retardation: Molecular characterization of the deleted region to 5q22.3q23.3. Am J Med Genet A 2005;132A:402-10. 57. Grant GB, Reef SE, Dabbagh A, Gacic-Dobo M, Strebel PM. Global progress toward rubella and congenital rubella syndrome control and elimination - 2000-2014. MMWR Morb Mortal Wkly Rep 2015;64:1052-5. 58. Martínez-Quintana E, Castillo-Solórzano C, Torner N, RodríguezGonzález F. Congenital rubella syndrome: A matter of concern. Rev Panam Salud Publica 2015;37:179-86. 59. Wang C, Li L, Cheng W. Anorectal malformation: The etiological factors. Pediatr Surg Int 2015;31:795-804. 60. Marcelis C, de Blaauw I, Brunner H. Chromosomal anomalies in the etiology of anorectal malformations: A review. Am J Med Genet A 2011;155A:2692-704. 61. AMBROSI V. [Congenital anorectal malformations]. Acta Chir Ital 1958;14:895-1000. 62. Vermes G, László D, Mátrai Á, Czeizel AE, Ács N. Maternal factors in the origin of isolated anorectal malformations—A population-based case-control study. J Matern Fetal Neonatal Med 2016;29:2316-21. 63. Wijers CH, van Rooij IA, Marcelis CL, Brunner HG, de Blaauw I, Roeleveld N. Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review. Birth Defects Res C Embryo Today 2014;102:382-400. 64. Zhang J, Tang XB, Wang WL, Yuan ZW, Bai YZ. Spatiotemporal expression of BMP7 in the development of anorectal malformations in fetal rats. Int J Clin Exp Pathol 2015;8:3727-34. 65. Moore SW. Associations of anorectal malformations and related syndromes. Pediatr Surg Int 2013;29:665-76. 66. Zhou D, Tan RJ, Zhou L, Li Y, Liu Y. Kidney tubular β-catenin signaling controls interstitial fibroblast fate via epithelial-mesenchymal communication. Sci Rep 2013;3:1878. 67. Douglas IS, Diaz del Valle F, Winn RA, Voelkel NF. Beta-catenin in the fibroproliferative response to acute lung injury. Am J Respir Cell Mol Biol 2006;34:274-85. 68. Kim MK, Maeng YI, Sung WJ, Oh HK, Park JB, Yoon GS, et al. The differential expression of TGF-β1, ILK and wnt signaling inducing epithelial to mesenchymal transition in human renal fibrogenesis: An immunohistochemical study. Int J Clin Exp Pathol 2013;6:1747-58. 69. Yoshida M, Tanaka M, Gomi K, Iwanaka T, Dehner LP, Tanaka Y. Fetal lung interstitial tumor: The first Japanese case report and a comparison with fetal lung tissue and congenital cystic adenomatoid


55


malformation/congenital pulmonary airway malformation type 3. Pathol Int 2013;63:506-9. 70. Al-Haggar M, Bakr A, Tajima T, Fujieda K, Hammad A, Soliman O, et al. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: Unusual clinical associations and novel claudin16 mutation in an Egyptian family. Clin Exp Nephrol 2009;13:288-94. 71. Türkmen M, Kasap B, Soylu A, Böber E, Konrad M, Kavukçu S. Paracellin-1 gene mutation with multiple congenital abnormalities. Pediatr Nephrol 2006;21:1776-8. 72. Hampson G, Konrad MA, Scoble J. Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): Compound heterozygous mutation in the claudin 16 (CLDN16) gene. BMC Nephrol 2008;9:12. 73. Jones NA, Jones SD. Management of life-threatening autonomic hyper-reflexia using magnesium sulphate in a patient with a high spinal cord injury in the intensive care unit. Br J Anaesth 2002;88:434-8. 74. Durlach J, Bac P, Durlach V, Bara M, Guiet-Bara A. Neurotic, neuromuscular and autonomic nervous form of magnesium imbalance. Magnes Res 1997;10:169-95. 75. Knohl SJ, Scheinman SJ. Inherited hypercalciuric syndromes: Dent’s disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1). Semin Nephrol 2004;24:55-60. 76. Basinko A, Giovannucci Uzielli ML, Scarselli G, Priolo M, Timpani G, De Braekeleer M. Clinical and molecular cytogenetic studies in ring chromosome 5: Report of a child with congenital abnormalities. Eur J Med Genet 2012;55:112-6. 77. Cohen O, Cans C, Cuillel M, Gilardi JL, Roth H, Mermet MA, et al. Cartographic study: Breakpoints in 1574 families carrying human reciprocal translocations. Hum Genet 1996;97:659-67. 78. Abeysinghe SS, Chuzhanova N, Krawczak M, Ball EV, Cooper DN. Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombinationassociated motifs. Hum Mutat 2003;22:229-44. 79. Clark DI, Howard PJ, Patterson A. Ocular findings in a patient with deletion short arm chromosome 5 (cri du chat) and ring chromosome 14. Trans Ophthalmol Soc U K 1986;105:723-5. 80. Kee CW, Lim P, Tan IK. Pseudohypoparathyroidism associated with cri du chat syndrome. Med J Aust 1976;2:344-5. 81. Murru D, Boccone L, Ristaldi MS, Nucaro AL. Cri du chat mosaicism: An unusual case of partial deletion and partial deletion/ duplication of the short arm of chromosome 5, leading to an unusual cri du chat phenotype. Genet Couns 2008;19:381-6. 82. Reamon-Buettner SM, Sattlegger E, Ciribilli Y, Inga A, Wessel A, Borlak J. Transcriptional defect of an inherited NKX2-5 haplotype comprising a SNP, a nonsynonymous and a synonymous mutation, associated with human congenital heart disease. PLoS One 2013;8:e83295. 83. Serra-Juhé C, Cuscó I, Homs A, Flores R, Torán N, Pérez-Jurado LA. DNA methylation abnormalities in congenital heart disease. Epigenetics 2015;10:167-77. 84. Wall PB, Traboulsi EI. Congenital abnormalities of the optic nerve: From gene mutation to clinical expression. Curr Neurol Neurosci Rep 2013;13:363. 85. Sun Y, Overvad K, Zhou WJ, Zhu JL, Olsen J. Cancer risks in parents who had a child with a congenital malformation. Birth Defects Res B Dev Reprod Toxicol 2013;98:154-63. 86. de Miranda DM, Dos Santos Júnior AC, Dos Reis GS, Freitas IS, Carvalho TG, de Marco LA, et al. PAX2 polymorphisms and congenital abnormalities of the kidney and urinary tract in a Brazilian pediatric population: Evidence for a role in vesicoureteral reflux. Mol Diagn Ther 2014;18:451-7.

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87. Goodman FR. Congenital abnormalities of body patterning: Embryology revisited. Lancet 2003;362:651-62. 88. Myers KA, Bello-Espinosa LE, Kherani A, Wei XC, Innes AM. TUBA1A mutation associated with eye abnormalities in addition to brain malformation. Pediatr Neurol 2015;53:442-4. 89. Uysal B, Dönmez O, Uysal F, Akacı O, Vuruşkan BA, Berdeli A. Congenital nephrotic syndrome of NPHS1 associated with cardiac malformation. Pediatr Int 2015;57:177-9. 90. Sa YJ, Kim YD, Moon SW, Kim CK, Ki CS. Occlusive vascular Ehlers-Danlos syndrome accompanying a congenital cystic adenomatoid malformation of the lung: Report of a case. Surg Today 2013;43:1467-9. 91. Millington KA, Mani H. Type 2 congenital pulmonary airway malformation and congenital nephrotic syndrome: Report of a new association. Pediatr Dev Pathol 2013;16:210-3. 92. Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol 2014;25:1917-22. 93. Gu YH, Kodama H, Kato T. Congenital abnormalities in Japanese patients with Menkes disease. Brain Dev 2012;34:746-9. 94. Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I, et al. Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel. PLoS One 2014;9:e93409. 95. Versteegh HP, Feitz WF, van Lindert EJ, Marcelis C, de Blaauw I. “This bicycle gives me a headache”, A congenital anomaly. BMC Res Notes 2013;6:412. 96. Tamura M, Amano T, Shiroishi T. The Hand2 gene dosage effect in developmental defects and human congenital disorders. Curr Top Dev Biol 2014;110:129-52. 97. Lozić B, Krželj V, Kuzmić-Prusac I, Kuzmanić-Šamija R, Čapkun V, Lasan R, et al. The OSR1 rs12329305 polymorphism contributes to the development of congenital malformations in cases of stillborn/ neonatal death. Med Sci Monit 2014;20:1531-8. 98. Weiner AS, Gordeeva LA, Voronina EN, Boyarskikh UA, Shabaldin AV, Filipenko ML. Polymorphisms in folate-metabolizing genes and risk of having an offspring with congenital anomalies in the West Siberian region of Russia: A case-control study. Prenat Diagn 2012;32:1041-8. 99. Wang D, Wang Q. [Advances in genetics of congenital malformation of external and middle ear]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2013;27:498-504. 100. DeBoer EM, Keene S, Winkler AM, Shehata BM. Identical twins with lethal congenital pulmonary airway malformation type 0 (acinar dysplasia): Further evidence of familial tendency. Fetal Pediatr Pathol 2012;31:217-24. 101. Tan HL, Glen E, Töpf A, Hall D, O’Sullivan JJ, Sneddon L, et al. Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Hum Mutat 2012;33:720-7. 102. Su P, Yuan Y, Huang Y, Wang W, Zhang Z. Anorectal malformation associated with a mutation in the P63 gene in a family with split hand-foot malformation. Int J Colorectal Dis 2013;28:1621-7. 103. Dundar M, Ozdemir SY, Fryns JP. A new syndrome: Multiple congenital abnormalities and mental retardation in two brothers. Genet Couns 2012;23:13-8. 104. Hemmat M, Yang X, Chan P, McGough RA, Ross L, Mahon LW, et al. Characterization of a complex chromosomal rearrangement using chromosome, FISH, and microarray assays in a girl with multiple congenital abnormalities and developmental delay. Mol Cytogenet 2014;7:50.



105. Cho SY, Ki CS, Jang JH, Sohn YB, Park SW, Kim SH, et al. Familial Xp22.33-Xp22.12 deletion deliniated by chromosomal micr array analysis causes propotionate short stature. Am J Med Genet A 2012;158A:1462-6. 106. Vissers LELM, Stankiewicz P, Yatsenko SA, Crawford E, Creswick H, Proud VK, et al. Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies. Hum Genet 2017;121:697-709. 107. St Pourcain B, Cents RA, Whitehouse AJ, Haworth CM, Davis OS, O’Reilly PF, et al. Common variation near ROBO2 is associated with expressive vocabulary in infancy. Nat Commun 2014;5:4831. 108. Kaplan KM, Spivak JM, Bendo JA. Embryology of the spine and associated congenital abnormalities. Spine J 2005;5:564-76. 109. Quina LA, Kuramoto T, Luquetti DV, Cox TC, Serikawa T, Turner EE. Deletion of a conserved regulatory element required for Hmx1 expression in craniofacial mesenchyme in the dumbo rat: A newly identified cause of congenital ear malformation. Dis Model Mech 2012;5:812-22. 110. Rattanasopha S, Tongkobpetch S, Srichomthong C, Kitidumrongsook P, Suphapeetiporn K, Shotelersuk V. Absent expression of the osteoblast-specific maternally imprinted genes, DLX5 and DLX6, causes split hand/split foot malformation type I. J Med Genet 2014;51:817-23. 111. Yu S, Yi H, Wang Z, Dong J. Screening key genes associated with congenital heart defects in Down syndrome based on differential expression network. Int J Clin Exp Pathol 2015;8:8385-93. 112. Ganaha A, Kaname T, Akazawa Y, Higa T, Shinjou A, Naritomi K, et al. Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism. J Hum Genet 2015;60:27-34. 113. Li C, Hao S, Wang H, Jin L, Qing F, Zheng F, et al. MicroRNA expression profiling and target genes study in congenital microtia. Int J Pediatr Otorhinolaryngol 2013;77:483-7. 114. Tassano E, Jagannathan V, Drögemüller C, Leoni M, Hytönen MK, Severino M, et al. Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion. Am J Med Genet A 2015;167A:537-44. 115. Liu Z, Wu N, Wu Z, Zuo Y, Qiu G. Advances in congenital vertebral malformation caused by genomic copy number variation. Zhonghua Wai Ke Za Zhi 2016;54:313-6. 116. Zhu X, Zhang Y, Wang J, Yang JF, Yang YF, Tan ZP. 576 kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy. Gene 2013;528:352-5. 117. Morcel K, Watrin T, Jaffre F, Deschamps S, Omilli F, Pellerin I, et al. Involvement of ITIH5, a candidate gene for congenital uterovaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome), in female genital tract development. Gene Expr 2012;15:207-14. 118. Gijsbers AC, Lew JY, Bosch CA, Schuurs-Hoeijmakers JH, van Haeringen A, den Hollander NS, et al. A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: Test arrays first. Eur J Hum Genet 2009;17:1394-402. 119. Shastry BS. Persistent hyperplastic primary vitreous: Congenital malformation of the eye. Clin Exp Ophthalmol 2009;37:884-90.

120. Ekici AB, Strissel PL, Oppelt PG, Renner SP, Brucker S, Beckmann MW, et al. HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina. Gene 2013;518:267-72. 121. Jin M, Zhu S, Hu P, Liu D, Li Q, Li Z, et al. Genomic and epigenomic analyses of monozygotic twins discordant for congenital renal agenesis. Am J Kidney Dis 2014;64:119-22. 122. Dai L, Deng Y, Li N, Xie L, Mao M, Zhu J. Discontinuous microduplications at chromosome 10q24.31 identified in a Chinese family with split hand and food malformation. BMC Med Genet 2013;14:45. 123. Aziz A, Irfanullah, Khan S, Zimri FK, Muhammad N, Rashid S, et al. Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families. Gene 2014;534:265-71. 124. Kempers MJ, Ozgen HM, Vulsma T, Merks JH, Zwinderman KH, de Vijlder JJ, et al. Morphological abnormalities in children with thyroidal congenital hypothyroidism. Am J Med Genet A 2009;149A:943-51. 125. Borg K, Bocian E, Stankiewicz P, Obersztyn E, Kruczek A, Nowakowska B, et al. Cytogenetic-molecular analysis of balanced chromosomal rearrangements in nine patients with intellectual disability, dysmorphic features and congenital abnormalities. Med Wieku Rozwoj 2006;10:227-46. 126. Petit F, Jourdain AS, Andrieux J, Baujat G, Baumann C, Beneteau C, et al. Split hand/foot malformation with long-bone deficiency and BHLHA9 duplication: Report of 13 new families. Clin Genet 2014;85:464-9. 127. Feng YM, Fang B. Current gene study in etiological analysis of congenital craniofacial abnormalities. Shanghai Kou Qiang Yi Xue 2007;16:215-8. 128. Leite M, Albieri V, Kjaer SK, Jensen A. Maternal smoking in pregnancy and risk for congenital malformations: Results of a Danish register-based cohort study. Acta Obstet Gynecol Scand 2014;93:825-34. 129. Borkar SA, Mahapatra AK. Split cord malformations: A two years experience at AIIMS. Asian J Neurosurg 2012;7:56-60. 130. Chavatte-Palmer P, Camous S, Jammes H, Le Cleac’h N, Guillomot M, Lee RS. Review: Placental perturbations induce the developmental abnormalities often observed in bovine somatic cell nuclear transfer. Placenta 2012;33:S99-S104. 131. Mahapatra AK. Split cord malformation—A study of 300 cases at AIIMS 1990-2006. J Pediatr Neurosci 2011;6:541-9. 132. Jindal A, Mahapatra AK. Split cord malformations–A clinical study of 48 cases. Indian Pediatr 2000;37:603-7. 133. Kumar R, Singh SN, Bansal KK, Singh V. Comparative study of complex spina bifida and split cord malformation. Indian J Pediatr 2005;72:109-15. 134. Kumar R, Bansal KK, Chhabra DK. Split cord malformation (SCM) in paediatric patients: Outcome of 19 cases. Neurol India 2001;49:128-33. 135. Venkataramana NK. Split cord malformations. J Pediatr Neurosci 2006;1:5-9.


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