Interstitial 22q13 deletions not involving SHANK3 gene: A new contiguous gene syndrome

Abstract

Phelan-McDermid syndrome (22q13.3 deletion syndrome) is a contiguous gene disorder resulting from the deletion of the distal long arm of chromosome 22. SHANK3, a gene within the minimal critical region, is a candidate gene for the major neurological features of this syndrome. We report clinical and molecular data from a study of nine patients with overlapping interstitial deletions in 22q13 not involving SHANK3. All of these deletions overlap with the largest, but not with the smallest deletion associated with Phelan-McDermid syndrome. The deletion sizes and breakpoints varied considerably among our patients, with the largest deletion spanning 6.9 Mb and the smallest deletion spanning 2.7 Mb. Eight out of nine patients had a de novo deletion, while in one patient the origin of deletion was unknown. These patients shared clinical features common to Phelan-McDermid syndrome: developmental delay (11/12), speech delay (11/12), hypotonia (9/12), and feeding difficulties (7/12). Moreover, the majority of patients (8/12) exhibited macrocephaly. In the minimal deleted region, we identified two candidate genes, SULT4A1 and PARVB (associated with the PTEN pathway), which could be associated in our cohort with neurological features and macrocephaly/hypotonia, respectively. This study suggests that the haploinsufficiency of genes in the 22q13 region beside SHANK3 contributes to cognitive and speech development, and that these genes are involved in the phenotype associated with the larger Phelan-McDermid syndrome 22q13 deletions. Moreover, because the deletions in our patients do not involve the SHANK3 gene, we posit the existence of a new contiguous gene syndrome proximal to the smallest terminal deletions in the 22q13 region.

Letter to the editor regarding Disciglio et al.: Interstitial 22q13 deletions not involving SHANK3 gene: A new contiguous gene syndrome

“…The use of the term "syndrome" indicates that there is a separate recognizable phenotype for the patients described by Disciglio et al [2014] but it does not appear that these patients can be phenotypically differentiated from patients with the terminal PMS chromosome rearrangements. Hypotonia, intellectual impairment, absent or delayed speech together with long eyelashes and hypoplastic brittle toenails do not paint a very distinct clinical picture.…”

“…Terminal deletions, interstitial deletions, unbalanced translocations, ring chromosomes, and more complex rearrangements have been associated with the clinical diagnosis of PMS. It might also be worth considering the complicated network of gene regulation involving microRNAs, such as hsa-mir-1249, which is deleted in all but one of the patients reported in the article by Disciglio et al [2014] and has among its predicted targets SHANK3 itself. While SHANK3 has been extensively studied as the causative or at least contributory gene, it is clear that many genes other than SHANK3 are involved in the pathogenesis of PMS [Sarasua et al, 2014b].…”

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

“…Overlap was seen with SLC39A11, PARVB, COL6A1 and GUSB. Mutations of PARVB, an actin-binding protein, have been described in association with developmental delay (Disciglio et al 2014), and COL6A1 is implicated in collagen myopathies and muscular dystrophy. Mutations of GUSB are the cause of Sly Syndrome, characterized by significant intellectual disability.…”

Phelan McDermid Syndrome

“…In the first report, the authors described a de novo reciprocal balanced translocation between chromosomes 12 and 22 with the breakpoint in exon 21 of SHANK3 in a child exhibiting the typical facial dysmorphic features, mild hypotonia, dolichocephaly, mild intellectual disability and severe speech impairment (Bonaglia et al, 2001). Only 12 individuals with interstitial deletions not involving SHANK3 have been reported thus far (Disciglio et al, 2014; Wilson et al, 2008). These patients display a phenotype partially overlapping with PMS, including developmental delay, hypotonia, overgrowth and macrocephaly (Disciglio et al, 2014; Wilson et al, 2008).…”

“…Only 12 individuals with interstitial deletions not involving SHANK3 have been reported thus far (Disciglio et al, 2014; Wilson et al, 2008). These patients display a phenotype partially overlapping with PMS, including developmental delay, hypotonia, overgrowth and macrocephaly (Disciglio et al, 2014; Wilson et al, 2008). However, the ASD symptomatology has not exhaustively been described in these patients: ASD was assessed only in three patients out of 12, among which two were reported as being affected (Disciglio et al, 2014).…”