A Novel DLG3 Mutation Expanding the Phenotype of X-Linked Intellectual Disability Caused by DLG3 Nonsense Variants.

The DLG3 gene is located at Xq13.1 and encodes SAP102, a member of the MAGUK protein family, extensively expressed in the brain and involved in synaptic function. Mutations in DLG3 are associated with a rare nonsyndromic form of X-linked intellectual disability (XLID) and have been described in 11 families to date. All affected males presented with intellectual disability, and some showed additional clinical features. The majority of female carriers were reported asymptomatic or mildly affected, due to skewed X-inactivation, rarely severely affected. We report a family, a boy and his mother, with a novel nonsense mutation in the DLG3 gene, c.1720C>T; p.Arg574*. The boy, hemizygous for the variant, showed intellectual disability, short stature due to growth hormone deficiency, dysmorphic features, and pectus excavatum. The mother, who presented with learning disabilities and borderline cognitive development, is a heterozygous carrier of the variant, which had arisen de novo. X-inactivation test was noninformative. This case report broadens the phenotypic spectrum of XLID caused by DLG3 nonsense variants. The dysmorphic features of the affected males may be more frequent than previously thought.

Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change? Two Novel Mutations and Literature Review.

The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in ACTB have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense ACTB mutations, c.208C>G (p.Pro70Ala) and c.511C>T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published ACTB missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in ACTB missense mutation carriers might supposedly be dependent on the conformational change of ACTB.