A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with a significant genetic component.
• Over 100 copy number variants and numerous genes have been implicated in ASD etiology.
• Establishing precise genotype-phenotype correlations is crucial for understanding ASD and developing targeted interventions.

Purpose of the Study:

• To identify recurrent, predicted damaging sequence-level variants in single genes associated with ASD.
• To investigate the genotype-phenotype correlations of a specific SHANK3 gene mutation in individuals with ASD.
• To determine the frequency and inheritance patterns of the identified SHANK3 variant in ASD cohorts.

Main Methods:

• Genome sequence data analysis and literature review to identify recurrent variants.
• Focus on variants affecting SHANK3, a known ASD-associated gene.
• Phenotypic evaluation of individuals carrying the identified SHANK3 variant (p.Ala1227Glyfs*69).

Main Results:

• Identified 18 individuals from 16 families with a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) in SHANK3.
• The p.Ala1227Glyfs*69 frameshift variant was found in 0.08% of ASD-affected individuals.
• Most mutations were de novo, but somatic mosaicism was observed in five individuals across three families.
• All 17 individuals formally tested for ASD carried the diagnosis, exhibiting variable expression of core ASD features.

Conclusions:

• The recurrent SHANK3 p.Ala1227Glyfs*69 frameshift variant is a significant, albeit rare, contributor to ASD.
• Variable phenotypic expression of this variant underscores the complexity of ASD.
• Understanding these recurrent mutational mechanisms is vital for accurate genetic counseling and timely early intervention in ASD.