ß 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 146A:1195 – 1199 (2008)
Clinical Report
Delineation of the Phenotype Associated With 7q36.1q36.2 Deletion: Long QT Syndrome, Renal Hypoplasia and Mental Retardation Rossella Caselli,1 Maria Antonietta Mencarelli,1 Filomena Tiziana Papa,1 Francesca Ariani,1 Ilaria Longo,1 Ilaria Meloni,1 Giuseppina Vonella,2 Maurizio Acampa,3 Alberto Auteri,3 Stefano Vicari,4 Alessandra Orsi,2 Giuseppe Hayek,2 Alessandra Renieri,1* and Francesca Mari1 1
Medical Genetics, University of Siena, Siena, Italy Child Neuropsichiatry, Azienda Ospedaliera Senese, Siena, Italy 3 Internal Medicine, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy 4 IRCCS, Ospedale Pediatrico Bambino Gesu`, S. Marinella, Roma, Italy 2
Received 25 June 2007; Accepted 12 November 2007
Terminal deletions of the long arm of chromosome 7 are well known and are frequently associated with hypotelorism or holoprosencephaly due to the involvement of the SHH gene located in 7q36.3. These deletions are easily detectable with routine subtelomeric MLPA analysis. Deletions affecting a more proximal part of 7q36, namely bands 7q36.1q36.2 are less common, and may be missed by subtelomeric MLPA analysis. We report a 9-year-old girl with a 5.27 Mb deletion in 7q36.1q36.2, and compare her to literature patients proposing a phenotype characterized by mental
retardation, unusual facial features, renal hypoplasia and long QT syndrome due to loss of the KCNH2 gene. These characteristics are sufficiently distinct that the syndrome may be diagnosed on clinical grounds. ß 2008 Wiley-Liss, Inc.
Key words: chromosome 7; array CGH; 7q deletion; long QT syndrome (LQTS); KCNH2 gene; fetal anticonvulsant syndrome; renal hypoplasia
How to cite this article: Caselli R, Mencarelli MA, Papa FT, Ariani F, Longo I, Meloni I, Vonella G, Acampa M, Auteri A, Vicari S, Orsi A, Hayek G, Renieri A, Mari F. 2008. Delineation of the phenotype associated with 7q36.1q36.2 deletion: Long QT syndrome, renal hypoplasia and mental retardation. Am J Med Genet Part A 146A:1195–1199.
INTRODUCTION
CLINICAL REPORT
More than 50 de novo deletions of the distal part of the long arm of chromosome 7 have been reported [Verma et al., 1992; Bisgaard et al., 2006], most of which involve the telomere and include the SHH gene, located in 7q36.3. The associated phenotype is characterized by low birth weight, pre- and postnatal growth retardation, developmental delay, microcephaly and holoprosencephaly. Recently, Bisgaard et al. [2006] described twin girls with an interstitial deletion in 7q34q36.2 of about 12.2 Mb, identified by HR-CGH who had mental retardation, unusual facial features, feeding problems, renal dysgenesis and long QT syndrome. We report the clinical and molecular characterization of a girl with a smaller deletion of the long arm of chromosome 7 involving bands q36.1 and q36.2, identified by array-CGH.
The proband is a 9 years and 9 months old girl who was the first child of 27-year-old nonconsanguineous parents (Fig. 1B). At the age of 14 years, the mother had required surgery for an intracerebral hematoma due to a frontal brain angioma. Eight years later, she developed seizures which were treated with phenytoin. During the first 6 weeks after conception, she took phenytoin and for
Grant sponsor: Telethon Foundation; Grant numbers: GGP05005, GGP06170Aspon. *Correspondence to: Dr. Alessandra Renieri, M.D., Ph.D., Medical Genetics, Molecular Biology Department, University of Siena, Viale Bracci, 2, 53100 Siena, Italy. E-mail:
[email protected] DOI 10.1002/ajmg.a.32197
American Journal of Medical Genetics Part A
1196
CASELLI ET AL.
FIG. 1. Comparison of facial characteristics between Fetal Phenytoin Syndrome at the age of 18 months (A), present case at 9 years and 2 months (B) and one of the twins reported by Bisgaard at 6 years and 6 months (C). Case (A) by [Moore et al., 2000] (Reprinted with permission of BMJ Publishing group Ltd.); case (C) by [Bisgaard et al., 2006] (Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
the following period of gestation she was treated with phenobarbital and carbamazepine. The girl was born after an uncomplicated pregnancy at 39 weeks of gestation with normal vaginal delivery. Her birth weight was 2,950 g (25–508 centile), length 47 cm (25–508 centile), OFC 33.5 cm (25–508 centile) and the Apgar score was 10 at 1 and 5 min, respectively. On the first day of life, she had seizures attributed to antiepileptic drug withdrawal. Doppler echocardiography was obtained because of a systolic heart murmur, and showed mild pulmonary stenosis. The ECG showed sinus tachycardia (115 bpm). The patient had delayed psychomotor development since she did not sit upright until 12 months, she was able to walk after 24 months, and she began to say her first words at the age of 3 years. Feeding difficulties and gastro-esophageal reflux has been referred in the first period of life. At the age of 5 months, right vesico-ureteral reflux was diagnosed for the recurrence of urinary tract infections. At 9 years renal scintigraphy showed hypodysplasia of the right kidney with important decrease of renal function (clearance ¼ 40 ml/min/1.73 m2 BSA). Ophthalmological and audiological evaluations were normal. A brain MRI at the age of 1 year revealed a mild enlargement of ventricules and a mild hypoplasia of the corpus callosum. The EEG was normal. The first karyotype (320 bands) was reported as a normal female. At 9 years and 2 months, her height was 130 cm (508 centile), weight was 32 kg (758 centile), and OFC was 53 cm (50–758 centile). She had blond, thick and coarse hair, prominent forehead, deep set eyes, posteriorly angulated ears with simple helix, bilateral epicanthal folds, flat nasal bridge, bulbous nasal tip, flat malar region, pointed chin, pectus excavatum and generalized hypertrichosis. Hands and feet are
small (38 centile). She is able to walk independently usually on tiptoe, with overall motor clumsiness. She has sleep disturbances with frequent night awakenings. A neuropsychological evaluation performed at the age of 9 years and 9 months, conducted using the WISC-III (Wechsler Intelligence Scale for Children, third edition) and the Vineland Adaptive Behavior Scales, Interview Edition, revealed moderate mental retardation with verbal IQ of 43, performance IQ of 49 and total IQ of 41. Her adaptive behavior revealed deficits in all tested areas, more evident in both receptive and expressive language. Lexicon and morphosyntax were poor both in comprehension and production. Moreover, phonological problems were evident and, in general, spontaneous language was poor and not very easily intelligible. Short term and long term memory and learning resulted severely impaired both for verbal and visual-spatial material. Finally, she showed a sustained attention deficit performing a cancellation task. Partially in contrast with this generalized pattern of severe impairment in cognitive functioning, praxic abilities were relatively preserved. After the identification of the pathogenic deletion by array CGH analysis, the revaluation of the electrocardiograms previously performed by the patient and additional ECGs revealed long QT intervals with QTc of 490 msec (QTc prolonged if >460 msec), in addition to sinus tachycardia already reported. QT dispersion and QTc dispersion were normal (40 and 50 msec, respectively). T waves were notched and of normal amplitude. Heart rate variability analysis showed also a sympathetic overactivity, associated with QTc prolongation. The total power spectrum of heart rate variability (from 0.03 to 0.40 Hz) was significantly lower in the patient
American Journal of Medical Genetics Part A DELINEATION OF THE PHENOTYPE ASSOCIATED WITH 7q36.1q36.2 DELETION 2
(521 msec ) in comparison with a control group of healthy children (n ¼ 40; total power ¼ 2,784– 7,606 msec2). The sympatho-vagal balance, expressed by the ratio LF/HF, showed an increase of sympathetic activity in the patient (6.35) in comparison with healthy children (0.42–1.38). MATERIALS AND METHODS Array-CGH Analysis
Array based CGH analysis was performed using commercially available oligonucleotide microarrays containing about 43,000 60-mer probes (Human Genome CGH Microarray 44B Kit, Agilent Technologies, Santa Clara, CA) as previously reported [Pescucci et al., 2007]. The average resolution is about 75–100 kb. Real-Time Quantitative PCR
Real-time quantitative PCR was performed to confirm array-CGH data. We used a pre-designed set of primers and probe specific for the SMARCD3 gene (7q36.1 locus) provided by the Assay-byDesign service (Applied Biosystems, Foster City, CA). Primers and probe were designed in exon 2 of the gene: SMARCD3_forward primer: 50 -CCATCTATGACTCCAGGTCTTCAG-30 ; SMARCD3_reverse primer: 50 -GGGCCCCAGAGCTTCT-30 ; SMARCD3_ TaqMan probe: 50 -CCACCGTGGTACAGGTAG-30 . Real-time quantitative PCR experiments were performed as previously reported [Pescucci et al., 2007]. Heart Rate Variability, QTc Interval and QTc Dispersion
12-lead ECG was recorded for 10 min by means of a commercially available imaging system (Cardioline ECT WS 2000; Remco Italia, Vignale-Milano, Italy). Algorithm, used for the heart rate variability analysis, was a spectral method (fast Fourier Transformation); three main spectral components were measured: very low frequency (VLF;
