Abstract
BackgroundAutism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype.MethodsClinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses.ResultsTwo males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis.ConclusionsPenetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.
Highlights
Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes
ASD diagnoses are made by expert clinicians using the Autism Diagnostic Interview (ADI) [13] and the Autism Diagnostic Observation Schedule (ADOS) [14] combined with clinical judgment
The mother has provided specific written consent for this case report. Phenotypes Both affected males were recruited into the study at the same time, one aged 9 years (III-3, hereafter “proband”) and the other 8 years (III-4) (Fig. 1). They had both been diagnosed with ASD at age 3 years, and on recruitment into the study, diagnostic clarification was sought with ADI-R and ADOS-G
Summary
Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. Our own whole genome sequencing (WGS) study (www.mss.ng), currently comprising 2620 ASD genomes from 2066 unique families, has identified a number of X chromosome genes in which rare predicted damaging mutations are enriched, including MECP2, NLGN3, NLGN4, and PCDH11X [7]. One such gene, RAB39B, has been described in the literature in association with X-linked ID along with variable phenotypic manifestations including ASD, seizures, macrocephaly, delayed psychomotor development, and early-onset Parkinson’s disease or Parkinsonism [8,9,10,11]. Through its trafficking role, RAB39B is known to mediate the surface expression of GluA2, a subunit of the glutamate AMPA receptor [12]
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