Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability.
Eur J Endocrinol
; 189(3): 387-395, 2023 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-37695807
ABSTRACT
OBJECTIVE:
Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature. DESIGN ANDMETHODS:
We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants.RESULTS:
We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04).CONCLUSION:
In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nanismo
Tipo de estudo:
Diagnostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Endocrinol
Assunto da revista:
ENDOCRINOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Brasil