TY - JOUR
T1 - Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants
AU - Yamada, Mamiko
AU - Ono, Masae
AU - Ishii, Tomohiro
AU - Suzuki, Hisato
AU - Uehara, Tomoko
AU - Takenouchi, Toshiki
AU - Kosaki, Kenjiro
N1 - Funding Information:
Grant‐in‐Aid for Early‐Career Scientists by JSPS KAKENHI, Grant/Award Number: JP19K17342; Initiative on Rare and Undiagnosed Diseases from the Japan Agency for Medical Research and Development, Grant/Award Number: JP20ek0109301 Funding information
Funding Information:
This work was supported by Initiative on Rare and Undiagnosed Diseases (grant number JP20ek0109301) from the Japan Agency for Medical Research and Development and JSPS KAKENHI, Grant‐in‐Aid for Early‐Career Scientists (grant number JP19K17342).
Publisher Copyright:
© 2021 Wiley Periodicals LLC.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - RNPC3
KW - growth hormone deficiency
KW - minor spliceosomopathy
KW - short stature
UR - http://www.scopus.com/inward/record.url?scp=85101877580&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101877580&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.62152
DO - 10.1002/ajmg.a.62152
M3 - Article
C2 - 33650182
AN - SCOPUS:85101877580
VL - 185
SP - 1836
EP - 1840
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 6
ER -