Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder

Abstract

Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable.

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

“…Consistent with our patient, all reported patients exhibited severe language delay, which represents a key SHANK2‐ related feature. In addition, in contrast to our case, nearly all previous patients showed autism; however, it is worth noting that a recent study has shown that ASD is not necessarily a constant clinical feature (Doddato et al, 2022 ). Additional features such as clinodactyly of both fifth fingers were frequently observed, consistent with 11q13 microdeletion patients and our proband (Table S2 ).…”

“…Several reports have revealed de novo loss‐of‐function variants in the SHANK2 gene, including microdeletions, nonsense mutations, and frameshift variants in patients with ASD and/or mild to moderate intellectual disability and severe language delay. Dysmorphic facial and hands features have also been observed, especially in patients with microdeletions and exonic deletions (Table S2 ) (Berkel et al, 2010 , 2012 ; Bowling et al, 2017 ; Caumes et al, 2020 ; Doddato et al, 2022 ; Guo et al, 2018 ; Leblond et al, 2012 , 2014 ; Marcou et al, 2017 ; Pinto et al, 2010 ; Wischmeijer et al, 2011 ; Zhou et al, 2019 ).…”

“…Among them, SHANK2 is a haploinsufficient gene. De novo variants of the SHANK2 gene have been found in patients with neurodevelopmental disorders, including four cases of exonic deletion (Berkel et al, 2010 ; Leblond et al, 2012 ; Pinto et al, 2010 ), three cases of frameshift variants (Bowling et al, 2017 ; Caumes et al, 2020 ), four cases of nonsense variants (Berkel et al, 2010 ; Doddato et al, 2022 ; Guo et al, 2018 ; Zhou et al, 2019 ), and one case of gene disruption resulting from a translocation (Leblond et al, 2014 ). Consistent with our patient, all reported patients exhibited severe language delay, which represents a key SHANK2‐ related feature.…”

Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans

“…As the patients described here appear to be more severely affected than those carrying heterozygous loss-of-function variants [55], our data suggest that nanocluster compaction is indeed a central aspect of Shank2 function. Furthermore, our data suggest a dominant pathomechanism, where the mutant Shank2 allel is dominant over the WT allel, and possibly also over the other two SHANK genes which send their gene products to the same postsynaptic sites.…”

“…We describe two patients with de novo missense variants in SHANK2 affected by a severe neurodevelopmental disorder, comprising moderate intellectual disability, delayed acquisition of motor and language skills, but also seizures (patient 1) and microcephaly (patient 2). Patients appear to be more severely affected than those carrying heterozygous loss-of-function variants, occurring e.g., trough frameshift or early stop mutations [55]. The variants alter two domains which are of central relevance for Shank protein function, i.e., the PDZ and SAM domains [3,13].…”