CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies

In a consanguineous Pakistani kinship afflicted with mild to moderate intellectual disability (ID), mild lissencephaly, brain atrophy and skeletal anomalies, we detected homozygous CRADD c.2T > G (p.Met1?) and USP44 c.873_886delinsT (p.Leu291Phefs*8), two good candidates 1.85-Mb apart that segregated with the disorder. Biallelic damaging variants in CRADD cause recessive mental retardation-34 (MRT34; MIM 614499) with mild to moderate ID, ?thin? lissencephaly, and variable megalencephaly and seizures. For USP44, only a single ID family has been reported with a homozygous deleterious variant, which is the same as the variant we detected. In affected individuals we present, at ages 29?32 years, clinical findings are similar yet not fully concordant with phenotypes for either gene considering the skeletal findings, and ID is not as severe as would be expected for defects in two genes with additive effect. Some variable CRADD-related features such as language impairment and seizures are not observed in the presented family. The presence of the two variants in the family is a very rare example of familial linked homozygous variants, and whether the damaging USP44 variant contributed to the disease in the family we present is not clear. As for the skeletal findings, facial dysmorphism and digestive problems, we did not find a candidate variant. This study is an example of both clinical variation and difficulty in variant detection and evaluation. Our findings highlight that even an extensive exome sequence analysis can fail to fully uncover the complex molecular basis of a syndrome even if potentially causative variants are identified.

Automated summary

This study identified two potentially pathogenic gene mutations in a family with intellectual disabilities, but the clinical manifestations of affected individuals did not fully align with the expected phenotypes for these two genes, highlighting the complexity within the family.