Dataset Information

Identification of HESX1 mutations in Kallmann syndrome.

ABSTRACT:

Objective

To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS).

Design

Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal ?.

Setting

Academic medical center.

Patient(s)

Two hundred seventeen patients with IHH/KS and 192 controls.

Intervention(s)

Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made.

Main outcome measure(s)

Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment.

Result(s)

Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present.

Conclusion(s)

HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.

SUBMITTER: Newbern K

PROVIDER: S-EPMC3888813 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of HESX1 mutations in Kallmann syndrome.

Newbern Kayce K Natrajan Nithya N Kim Hyung-Goo HG Chorich Lynn P LP Halvorson Lisa M LM Cameron Richard S RS Layman Lawrence C LC

Fertility and sterility 20130301 7

<h4>Objective</h4>To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS).<h4>Design</h4>Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω.<h4>Setting</h4>Academic medical center.<h4>Patient(s)</h4>Two hundred seventeen patients with IHH/KS and 192 controls.<h4>Inter ...[more]

PMID: 23465708

Similar Datasets

Project description:BackgroundKallmann 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.MethodsA 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.ResultsANOS1 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)chr8:g.36140000_38460000del was judged as pathogenic according to the ACMG & ClinGen technical standards.ConclusionsHerein, 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)chr8:g.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.

Dataset Information

Identification of HESX1 mutations in Kallmann syndrome.

Objective

Design

Setting

Patient(s)

Intervention(s)

Main outcome measure(s)

Result(s)

Conclusion(s)

Publications

Identification of HESX1 mutations in Kallmann syndrome.

Similar Datasets

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