Submission Details

The RPL10 gene, encoding a ribosomal protein, was first suggested to be implicated in X-linked autism in 2006 by Klauk et al. (PMID: 16940977). They reported two C-terminal missense variants in two independent families with two males each with autism spectrum disorder. Although the authors suggested these two variants resulted in hypomorphic alleles with respect to the regulation of the translation process when expressed in yeast, they were not scored as evidence because subsequent rescue studies in zebrafish showed no loss of function (PMID: 25316788). Four other missense variants in RPL10 have been reported in the literature: 1) Brooks et al. (2014, PMID: 25316788) and Bourque et al. (2018, PMID: 29066376) reported the same N-terminal missense variant (p.Lys78Glu) in affected males from 2 unrelated families. Common clinical features included intellectual disability, seizures, microcephaly, hypotonia, hearing loss, ataxia, dysmorphic facial features, cardiac defects, and short stature. In a zebrafish model with knockdown of rpl10, p.Lys78Glu was not able to rescue the microcephaly phenotype, suggesting a loss of function variant (PMID: 25316788). 2) Another missense variant (p.Gly161Ser) was reported by Thevenon et al. (2015, PMID: 25846674) in a family with 4 males with syndromic intellectual disability. Although this variant has not been functionally validated, a mutation in yeast affecting the same amino acid results in loss of function (PMID: 9933353). 3) Zanni et al. (2015, PMID: 26290468) reported an additional missense variant (p.Ala64Val) in 2 maternal male cousins with syndromic intellectual disability. Although they shared some features with the previously reported patients, notably ataxia, they also exhibited other features not reported previously, such as spondylo-epiphyseal dysplasia. In a yeast model, this variant was shown to exhibit an increase in translationally active ribosomes, unlike previously reported variants. 4) More recently, Cappuccio et al. (2022, PMID: 35876338) reported a recurrent missense variant (p.Arg32Leu) in RPL10 in 4 male children from 3 unrelated families. In addition to intellectual disability, dysmorphic features, and progressive postnatal microcephaly, the 4 boys had retinal abnormalities. No functional studies were performed, but the recurrence of the variant and the phenotypic overlap with previously reported cases supports a deleterious effect.

In addition, two further missense variants have been reported in ClinVar: 5) A maternally-inherited missense variant (p.Gly161Asp, Accession: SCV001814517.1 ) in a male with developmental delay, seizure-like activity, microcephaly, hypotonia, growth delay, and dysmorphic features. Functional studies in yeast suggest a damaging effect (PMID: 9933353). A different variant affecting the same amino acid was reported previously in a family with 4 affected individuals (Thevenon et al. 2015, PMID: 25846674). 6) A de novo missense variant (p.Arg3His, Accession: SCV000589527.2 ) in a male with intellectual disability, developmental delay, and microcephaly.

This gene-disease relationship is also supported by a zebrafish model with decreased head size, decreased translation activity and increased apoptosis in the brain (PMID: 25316788).

In summary, there is definitive evidence supporting the relationship between RPL10 and X-linked syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 28, 2024. This gene-disease pair was originally evaluated in March 2018 and given a Limited classification. It was reevaluated on January 20, 2021 and given a Moderate classification due to changes in scoring practices. As a result of a further reevaluation on November 28, 2024, the classification increased from Moderate to Definitive with the addition of new cases (PMID: 35876338 and ClinVar).