RALA encodes a small Ras-like GTPase. RALA was first reported in relation to autosomal dominant complex neurodevelopmental disorder (also known as Hiatt-Neu-Cooper neurodevelopmental disorder) in 2018 (Hiatt et al., PMID: 30500825). The main phenotypic features include intellectual disability, speech problems, autism spectrum disorder, hypotonia, structural brain abnormalities, seizures, dysmorphic features, skeletal anomalies, delayed growth, and macrocephaly. Seven de novo variants (six missense and one inframe) reported in 13 individuals are included in this curation (PMIDs: 30500825, 30761613, 33875846, 35846790). All the variants are located in the GTP/GDP-binding region of RALA. Two variants are recurrent, p.Val25Met and p.Lys128Arg. Functional studies showed that four missense variants exhibited loss of function, while two resulted in gain of function (PMIDs: 30500825, 35846790). One of the missense variants leading to gain of function is a brain somatic variant identified in a child with epilepsy and focal cortical dysplasia type II (PMID: 35846790).
This gene-disease relationship is also supported by experimental evidence. Biallelic loss-of-function variants in RALGAPA1, encoding the catalytic subunit of the RalGAP complex that regulates RALA activity, cause a neurodevelopmental disorder with features overlapping those caused by RALA variants and lead to a constitutive activation of RALA in patient cells (PMID: 32004447). Additionally, in utero electroporation of the RALA c.G482A somatic variant (identified in an individual with focal cortical dysplasia) in the embryonic mouse brain induced abnormal cortical neuron migration (PMID: 35846790).
In summary, there is definitive evidence supporting the relationship between RALA and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 3, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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