Edition of 09 February 2018

The authors provided evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency resulted in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations caused an overgrowth syndrome with intellectual disability. They further expanded the phenotypic spectrum of KMT2B-related disorders and showed that some individuals could have severe developmental delay without dystonia at least until mid-childhood. Additionally, they described a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognisable syndrome with developmental delay, facial dysmorphism, and camptodactyly.

The authors used exome sequencing in a multiplex family and three simplex case subjects with an atypical association of Leber congenital amaurosis with early-onset hearing loss. They identified two heterozygous mutations affecting the TUBB4B gene.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which the authors suggested to name Alkuraya-Kučinskas syndrome. Shared phenotypic features representing the cardinal characteristics of this syndrome combined brain atrophy with clubfoot and arthrogryposis. Affected individuals presented with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support.