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

• Published in: Molecular autism 2018-04, Vol.9 (1), p.31-20, Article 31
• Main Authors: De Rubeis, Silvia, Siper, Paige M, Durkin, Allison, Weissman, Jordana, Muratet, François, Halpern, Danielle, Trelles, Maria Del Pilar, Frank, Yitzchak, Lozano, Reymundo, Wang, A Ting, Holder, Jr, J Lloyd, Betancur, Catalina, Buxbaum, Joseph D, Kolevzon, Alexander
• Format: Article
• Language: English
• Subjects: 22q13 deletion syndrome; Autism spectrum disorder; Genetics; Human health and pathology; Life Sciences; Phelan-McDermid syndrome; Phenotype; Psychiatrics and mental health; Sequence variants; SHANK3
• ISSN: 2040-2392; 2040-2392
• DOI: 10.1186/s13229-018-0205-9

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. We provide detailed clinical and genetic data on 17 individuals carrying mutations in . We also review 60 previously reported patients with pathogenic or likely pathogenic variants, often lacking detailed phenotypic information. 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. Haploinsufficiency of 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 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 .