Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants

Abstract

Some mammalian genes contain both major and minor introns, the splicing of which require distinctive major and minor spliceosomes, respectively; these genes are referred to as minor intron containing‐genes. RNPC3 (RNA‐binding domain‐containing protein 3) is one of the proteins that are unique to the minor spliceosome U11/U12 di‐snRNP. Only two families with biallelic pathogenic variants in the RNPC3 gene encoding the protein have been reported so far, and the affected members in both families had proportional short stature. While the affected members of the originally identified family did not have intellectual disability, the patients from the other family exhibited intellectual disability. Here, we report on a patient with severe primordial microcephalic dwarfism and intellectual disability who carried compound heterozygous variants in RNPC3 (NM_017619.3): c.261dup, p.Leu88Thrfs*11 and c.1228T>G, p.Phe410Val. The single nucleotide substitution c.1228T>G had a very high predictive score for pathogenicity: the p.Phe410 residue is highly conserved down to fish. Based on ACMG (American College of Medical Genetics and Genomics) guideline, this non‐synonymous variant was scored as likely pathogenic. This documentation of yet another patient with biallelic RNPC3 variants exhibiting intellectual disability lends further support to the notion that intellectual disability is a key feature of the spectrum of RNPC3‐related disorders.

Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

“…She was reported to be prepubertal at age 11y; GHD and prolactin deficiency were documented but biochemical data of gonadotropin concentrations were not provided. 24 …”

“…Since the first three publications of RNPC3 variants in cases with GHD, 14 , 23 , 24 we have identified 12 more patients, four compound heterozygotes for p.P474T together with a second disruptive change and eight homozygotes with p.L483F variant. The first three Spanish siblings reported 14 presented with severe isolated GHD at ages 14y, 7·6y and 5·5y, respectively.…”

A homozygous Y443C variant in the RNPC3 is associated with severe syndromic congenital hypopituitarism and diffuse brain atrophy

“…This suggests that aberrant/abnormal splicing of genes containing U12-type introns may impair global cell proliferation in brain. However, previous patients with RNPC3 mutations were also reported to have less severe microcephaly (Argente et al, 2014), although Yamada et al (2021), described a patient with severe microcephaly and growth retardation due to compound heterozygous RNPC3 mutations. Cranial imaging findings of our patient support the role of RNPC3 in global brain development.…”

“…The minor spliceosome plays a role in the splicing of minor (U12-type) introns, which are present in $700-800 genes in humans and represent about 0.35% of all introns (Turunen et al, 2013). Variants in RNPC3 have previously been associated with isolated growth hormone deficiency (Argente et al, 2014;Gucev et al, 2015;Yamada et al, 2021). Additionally, three siblings with novel biallelic RNPC3 variants were recently reported to manifest panhypopituitarism (Verberne et al, 2020).…”

Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

“…She was reported to be prepubertal at age 11y; GHD and prolactin deficiency were documented but biochemical data of gonadotropin concentrations were not provided. 24 Since the first three publications of RNPC3 variants in cases with GHD, 14,23,24 we have identified 12 more patients, four compound heterozygotes for p.P474T together with a second disruptive change and eight homozygotes with p.L483F variant. The first three Spanish siblings reported 14 U12-type introns are particularly present in genes related to 'information processing functions', such as DNA replication and repair, transcription, RNA processing, and translation.…”