Edition of 30 March 2021

A new study published in the American Journal of Human Genetics identified fourteen males from nine families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability, distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with intellectual disability across three generations. RLIM is the only gene common to our duplications. This study showed that that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

A new study published in the American Journal of Human Genetics identified four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. This study showed that SMG8 and SMG9 deficiency results in overlapping developmental disorders.

A new study published in the American Journal of Human Genetics identified seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual.

A new study published in Genetics in Medicine identified variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with Nicolaides-Baraitser syndrome. Of 20 individuals, 14 individuals showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability or blepharophimosis intellectual disability syndrome (BIS), with SMARCA2 variants associated with BIS localized outside the helicase domains. This study described a novel recognizable syndrome with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from Nicolaides-Baraitser syndrome.