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