A Genotype-First Approach in Individuals with Variable Intellectual Disability Permits BRWD3 Mutations’ Diagnosis

Background: Since the first description of a BRWD3-related phenotype in 2007, 21 additional families have been reported with intellectual disability (ID).Methods: Using exome sequencing (ES) and international datasharing, we identified 14 new unrelated individuals with a pathogenic BRWD3 variant (12 males and 2 females one with skewed X-inactivation). Including the 31 previously individuals published in the literature with clinical data available, we describe the phenotype of 43 males and 2 females, with 32 different BRWD3 variants.Results: Most common features in males (excluding the one with the mosaic variant) include ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females present with macrocephaly, speech delay and epilepsy while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo.Conclusion: This study demonstrates that the BRWD3 -related phenotype could be non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach however allows the diagnosis of the BRWD3 -related phenotype. The refined clinical features presented here will prove useful for reverse phenotyping.