ClinGen Dosage Sensitivity Curation Page

RPL10

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)

Haploinsufficiency phenotype comments:

Susceptibility to X-linked autism-5 (AUTSX5; MIM #300847). There are no loss of function variants described in RPL10 . Missense variants (c.639C>G p.H213Q) have been found in a few male patients with autism and their unaffected female relatives. However, these individuals had normal transcription and association studies have failed to find significant results (see PMID: 21567917). Missense variants segregated with X-linked syndromic mental retardation-35 (MRXS35; MIM #300998) (see PMID's: Brooks et al. 2014, PMID: 25316788; Thevenon et al. 2015, PMID: 25846674; Zanni et al. 2015 PMID: 26290468; Bourque et al PMID: 29066376 ). All females showed fully skewed X inactivation of the variant-bearing X chromosomes. Brooks et al. had functional studies in zebrafish, knockdown of rpl10 gene resulted in microcephaly. Brooks et al. included three males (c.232A>G; p.K78E) with severe central nervous system defects, including microcephaly and seizures in combination with growth retardation and a multitude of additional congenital defects. Zebrafish studies showed rpl10 suppression decreases head size, reduced bulk translation and increased apoptosis in the brain, demonstrating p.K78E as a LOSS OF FUNCTION variant. Thevenon et al. included four males (c.481G>A; p.G161S) with intellectual disability, psychomotor delay with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. Zanni et al. included two cousins (c.191C>T;p.A64V) presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Bourque et al. (c.232A>G), de novo, with severe ID, absent speech, microcephaly, ataxia, dysmorphic facial features, and refractory, early onset seizure disorder. This paper also reviews the literature, showing the spectrum of features for six unrelated families with 14 affected males (including Brooks, Thevenon, and Zanni). The common feature of all 14 + de novo (so 15) is developmental or intellectual disability. Variants at the C-terminus (p.L206M and p.H213Q) appear to be associated with autism, the more N-terminal (p.A64V, p.K78E, and p.G161S) results in a syndrome that includes microcephaly, genitourinary abnormalities, neurological findings including seizures, hypotonia and ataxia with and without cerebellar atrophy.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.