Elsevier

European Journal of Medical Genetics

Volume 52, Issue 5, September–October 2009, Pages 328-332
European Journal of Medical Genetics

Short report
Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3

https://doi.org/10.1016/j.ejmg.2009.05.004Get rights and content

Abstract

Background

The 22q13.3 deletion syndrome (or Phelan-McDermid syndrome, MIM 606232) is characterized by developmental delay, absent or severely delayed speech, neonatal hypotonia, autistic behavior, normal to accelerated growth, and minor dysmorphic facial features. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3, ACR and RABL2B), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms.

Objective

We describe the molecular characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with the 22q13.3 deletion syndrome.

Methods

Clinical work-up included clinical histories, physical, neurological, and ophthalmological examinations, and imaging of the brain. Commercially available MLPA for subtelomeric analysis, FISH specific probes and quantitative real-time PCR were used to characterize the rearrangement.

Results

Subtelomere analysis by MLPA showed a discrepancy between P036B and P070 kits (MCR Holland®): the P070 MLPA 22q probe (targeting the ARSA gene) showed a deletion but the P036B one (targeting the RABL2B gene) showed a normal result. FISH analysis using LSI TUPLE1/LSI ARSA (Vysis®) probes confirmed deletion of ARSA, whereas FISH with N25/N85A3 (Cytocell®) probes, targeting the SHANK3 locus was normal. Supplemented FISH analysis using BAC clones allowed us to specify the centromeric breakpoint region of the interstitial deletion between clones RP11-354I12 and RP11-232E17, at less than 2 Mb from the telomere. Quantitative real-time PCR of exon 5, 22 and 24 and intron 9 of SHANK3 showed that the telomeric breakpoint occurred between intron 9 and exon 22.

Conclusions

These data highlight the difficulty of performing an appropriate test aimed at looking for cryptic 22q13.3 deletion. Furthermore, the molecular characterization of this interstitial 22q13.3 deletion contributes to the clinical and genetic delineation of the 22q13.3 deletion syndrome.

Introduction

The 22q13.3 deletion syndrome (MIM 606232) – commonly referred to as del 22qter syndrome or Phelan-McDermid syndrome [15] – is the second most common subtelomeric imbalance found in patients with mental retardation after 1p36 deletion [16]. The first case of pure 22q13.3 deletion was the result of a familial pericentric inversion of chromosome 22 [17]. The loss of terminal 22q13.3 can be subtle and can go undetected by routine chromosome analysis. FISH is often required to confirm the presence of this deletion. Some identifications of the 22qter deletion have been serendipitously made in patients referred for DiGeorge/velo-cardio-facial syndrome (DiGeorge/VCSF) by the absence of signals from the 22q13 control probe from commercially available VCSF/DGS FISH probe kits [14]. Even if most 22qter deletions are isolated, 20% are the result of an unbalanced translocation (8/37 [9]). Their phenotype is complicated by the presence of material gain from the other chromosome involved in the translocation. Furthermore, 22qter deletion can rarely be associated with ring chromosome 22, usually found in mosaic state [10].

The phenotype associated with 22q13.3 deletion consists of global developmental delay, absent or severely delayed speech, neonatal hypotonia, normal to accelerated growth, autistic behavior and minor dysmorphic features including large head circumference [4], [8], [11], [13].

Interstitial 22q13 deletions have been reported in three cases [6], [18] (Fig. 2F). The distal breakpoints were identified at least 5 Mb away from the telomere, suggesting that these interstitial deletions should be differentiated from the subtelomeric 22q13.3 deletion syndrome. However, phenotypic similarity with terminal 22q13.3 deletions allowed the authors to conclude that the clinical picture of the 22q13.3 deletion syndrome is non-specific [18].

Molecular characterization of 22q13.3 deletions enabled researchers to define a minimal critical region [19] and a recurrent breakpoint within intron 8 of the SHANK3 gene (also known as PROSAP2) [3]. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3, ACR and RABL2B), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms. Indeed, it was shown that the SHANK3 gene had been disrupted by a de novo balanced translocation in a child with all the features of the 22q13.3 deletion syndrome [2]. Furthermore, the expression of SHANK3 predominates in the cerebral cortex and in the cerebellum. SHANK3 encodes a scaffolding protein found in the dendritic spines of excitatory synapses, where it may function as a master organizer of the postsynaptic density (PSD) complex [1]. Recently, de novo mutations of a single copy of SHANK3 were found in patients with an autism spectrum disorder (ASD) from three distinct families [5], [7], [12].

We report here the characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with 22q13.3 deletion syndrome.

Section snippets

Patient

The patient was referred to the Clinical Genetics Department of the University Hospital of Tours for unexplained mental retardation. We obtained a detailed clinical history and carried out physical and ophthalmological examinations, as well as brain imaging studies for the patient. Informed consent was obtained from her parents.

Genetic analysis

The standard karyotype and molecular genetic study of fragile X were previously shown to be normal. Subtelomeric analysis using the MLPA showed abnormal findings, which

Clinical findings

The patient was the second daughter of non-consanguineous French parents aged 27 and 32 years at the time of conception. The older sister and younger brother were healthy. The first pregnancy of the mother ended with an unexplained stillbirth at 36 weeks. Apart from intra-uterine growth retardation, no morphological abnormality was noted by ultrasonography. Fetopathological examination was declined and the fibroblast culture for fetal karyotype failed. Family history was otherwise unremarkable.

Discussion

We report a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child presenting a phenotype concordant with the classical presentation of 22q13.3 deletion syndrome. Table 2 compares clinical features of our patient with those classically associated with 22q13.3 deletion. Although the deletion was interstitial, her phenotype was compatible with a 22q13.3 deletion syndrome. Disruption of the SHANK3 gene is likely to explain the clinical picture. Our case is the first report

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