TL;DR
A patient with cerebellar atrophy, ataxia, and global developmental delay is described, and trio exome sequencing identified compound heterozygous variants in the final subunit EXOSC6.
Overall, EIF1AX is a novel gene for which loss-of-function variants appear to produce syndromic neurodevelopmental disorders in males, and its pathogenicity was evaluated using a molecular dynamic simulation and transgenic Drosophila models.
This finding may represent the first reported Saudi family with a SYNE1 mutation associated with Autosomal Recessive Spinocerebellar Ataxia type 8 and Autosomal Recessive Cerebellar Ataxia type 1 and highlights the utility of molecular diagnostics.
The data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene that results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.
A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.
Tetratricopeptide Repeat Domain 14 plays a crucial role in RNA metabolism during neurodevelopment, and that the p.His30Arg variant impairs its function, possibly leading to a neurodevelopmental disorder within the lissencephaly spectrum.
There is moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype, suggesting that the allelic and clinical heterogeneity of HARS1‐related disease is expanded.