Mutation spectrum of Kallmann syndrome: identification of five novel mutations across ANOS1 and FGFR1.
Reprod Biol Endocrinol
; 21(1): 23, 2023 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-36859276
ABSTRACT
BACKGROUND:
Kallmann syndrome (KS) is a common type of idiopathic hypogonadotropic hypogonadism. To date, more than 30 genes including ANOS1 and FGFR1 have been identified in different genetic models of KS without affirmatory genotype-phenotype correlation, and novel mutations have been found.METHODS:
A total of 35 unrelated patients with clinical features of disorder of sex development were recruited. Custom-panel sequencing or whole-exome sequencing was performed to detect the pathogenic mutations. Sanger sequencing was performed to verify single-nucleotide variants. Copy number variation-sequencing (CNV-seq) was performed to determine CNVs. The pathogenicity of the identified variant was predicted in silico. mRNA transcript analysis and minigene reporter assay were performed to test the effect of the mutation on splicing.RESULTS:
ANOS1 gene c.709 T > A and c.711 G > T were evaluated as pathogenic by several commonly used software, and c.1063-2 A > T was verified by transcriptional splicing assay. The c.1063-2 A > T mutation activated a cryptic splice acceptor site downstream of the original splice acceptor site and resulted in an aberrant splicing of the 24-basepair at the 5' end of exon 8, yielding a new transcript with c.1063-1086 deletion. FRFR1 gene c.1835delA was assessed as pathogenic according to the ACMG guideline. The CNV of del(8)(p12p11.22)chr8g.36140000_38460000del was judged as pathogenic according to the ACMG & ClinGen technical standards.CONCLUSIONS:
Herein, we identified three novel ANOS1 mutations and two novel FGFR1 variations in Chinese KS families. In silico prediction and functional experiment evaluated the pathogenesis of ANOS1 mutations. FRFR1 c.1835delA mutation and del(8)(p12p11.22)chr8g.36140000_38460000del were assessed as pathogenic variations. Therefore, our study expands the spectrum of mutations associated with KS and provides diagnostic evidence for patients who carry the same mutation in the future.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas da Matriz Extracelular
/
Síndrome de Kallmann
/
Receptor Tipo 1 de Fator de Crescimento de Fibroblastos
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Diagnostic_studies
/
Guideline
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Reprod Biol Endocrinol
Assunto da revista:
ENDOCRINOLOGIA
/
MEDICINA REPRODUTIVA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China