Identification of known and new candidate molecular causes of inherited neurodevelopmental disorders

Abstract

Intellectual disability (ID) is a rare neurodevelopmental disorder estimated to affect at least 1% of the population. ID is defined as “a disorder with onset during the developmental period that includes both intellectual and adaptive functioning deficits in conceptual, social and practical domains. ID is a complex and highly variable disorder, often associated with a number of other conditions such as microcephaly and neurological impairment. Identifying genes responsible for ID will not only aid diagnosis and genetic counselling efforts, but also elevate our understanding of the complex mechanisms and genes crucial for normal brain development. Consanguineous populations are often enriched for autosomal recessive disorders such as ID. With this in mind, an investigative strategy was designed to identify the underlying genetic cause of ID within four families identified through an ongoing translational community research program based at UEMS. Each family has at least two individuals affected with varying ID phenotypes. Single nucleotide polymorphism mapping and whole exome sequencing was used to identify potential candidate pathogenic variants within shared autozygous regions and genome wide. A putative diagnosis has been made within two of the families, with one family harbouring a known variant within ALG1; which is known to cause a rare autosomal recessive congenital disorder of glycosylation, and the other family harbouring a novel variant within an ARHGAP gene; which has recently been implicated in neurodevelopmental disorders. The other two families require further research, however potential novel variants as well as chromosomal 5 variations have been identified. Through this collaborative study we have shown how important community-based research programmes are in defining the genetic causes of rare disorders.