Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations

Abstract

BackgroundPhelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking.MethodsWe provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information.ResultsSHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems.ConclusionsHaploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0205-9) contains supplementary material, which is available to authorized users.

Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan McDermid syndrome and autism

“…Our group has previously shown that SHANK3 point mutations are sufficient to convey a PMS phenotype [4], although larger deletion sizes have been associated with a more severe range of PMS manifestations [6, 7, 41]. Here, we find that differences in SHANK3 deletion size have a significant dosage effect on 50 genes that span the largest deletion in our dataset.…”

“…1% of ASD diagnoses [1–3]. PMS is caused by heterozygous 22q13.3 deletions or mutations leading to haploinsufficiency of the SHANK3 gene [2, 4–6]. Clinical manifestations of PMS include ASD, global developmental delay, severe to profound intellectual disability (ID), motor abnormalities, delayed or absent speech, and epilepsy [2, 6, 7].…”

Environmental enrichment has minimal effects on behavior in the Shank3 complete knockout model of autism spectrum disorder

“…We did not observe any sex differences in this study or in our previous characterization of the Shank3 knockout mice. Although human males are more likely to be diagnosed with ASD compared to females, there is no apparent sex bias for SHANK3 mutations (De Rubeis et al, ; Sarasua et al, ). Another consistent finding from both this study and our previous characterization of the Shank3 ∆e4–22 mice is a lack of a strong phenotype in heterozygous animals.…”

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

“…While the literature demonstrating a gut-brain connection in ASD is robust and continues to grow 47 , there have been relatively few studies utilizing genetic mouse models carrying ASD associated mutations combined with manipulations of the microbiome to model gene x microbiome interactions. For our studies, we chose a murine model which carries a deletion of the Shank3 gene and is generally used as a model for Phelan-McDermid syndrome -in which patients are hemizygous for the Shank3 gene 5 . While there are numerous mouse lines carrying various Shank3 deletions, we utilized the recently characterized model with a deletion of exons 4-22 which lacks all functional isoforms of the Shank3 protein 22 .…”

“…Studies examining the composition of the microbiome in patients with ASD have repeatedly found that patients have differences in microbiome composition [9][10][11] , but specific microbial changes associated with a diagnosis have varied between studies. Additionally, patients with both idiopathic and syndromic forms of ASD have gastrointestinal issues at rates much higher than the general population 5,11 .…”