The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

Séverine Marcos; Julie Sarfati; Chrystel Leroy; Corinne Fouveaut; Philippe Parent; Chantal Metz; Slawomir Wolczynski; Marion Gérard; Eric Bieth; François Kurtz; Odile Verier-Mine; Laurence Perrin; Françoise Archambeaud; Sylvie Cabrol; Patrice Rodien; Hanne Hove; Trine Prescott; Didier Lacombe; Sophie Christin-Maitre; Philippe Touraine; Sylvie Hieronimus; Didier Dewailly; Jacques Young; Michel Pugeat; Jean-Pierre Hardelin; Catherine Dodé

doi:10.1210/jc.2014-2110

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

Séverine Marcos, Julie Sarfati, Chrystel Leroy, Corinne Fouveaut, Philippe Parent, Chantal Metz, Slawomir Wolczynski, Marion Gérard, Eric Bieth, François Kurtz, Odile Verier-Mine, Laurence Perrin, Françoise Archambeaud, Sylvie Cabrol, Patrice Rodien, Hanne Hove, Trine Prescott, Didier Lacombe, Sophie Christin-Maitre, Philippe TouraineSylvie Hieronimus, Didier Dewailly, Jacques Young, Michel Pugeat, Jean-Pierre Hardelin, Catherine Dodé

Afdeling for Genetik

75 Citationer (Scopus)

Abstract

CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown.

OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients.

DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7.

RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families.

CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

Originalsprog	Engelsk
Tidsskrift	The Journal of clinical endocrinology and metabolism
Vol/bind	99
Udgave nummer	10
Sider (fra-til)	E2138-43
ISSN	0021-972X
DOI	https://doi.org/10.1210/jc.2014-2110
Status	Udgivet - okt. 2014

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10.1210/jc.2014-2110

Citationsformater

Marcos, S., Sarfati, J., Leroy, C., Fouveaut, C., Parent, P., Metz, C., Wolczynski, S., Gérard, M., Bieth, E., Kurtz, F., Verier-Mine, O., Perrin, L., Archambeaud, F., Cabrol, S., Rodien, P., Hove, H., Prescott, T., Lacombe, D., Christin-Maitre, S., ... Dodé, C. (2014). The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients. The Journal of clinical endocrinology and metabolism, 99(10), E2138-43. https://doi.org/10.1210/jc.2014-2110

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients. / Marcos, Séverine; Sarfati, Julie; Leroy, Chrystel et al.
I: The Journal of clinical endocrinology and metabolism, Bind 99, Nr. 10, 10.2014, s. E2138-43.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Marcos, S, Sarfati, J, Leroy, C, Fouveaut, C, Parent, P, Metz, C, Wolczynski, S, Gérard, M, Bieth, E, Kurtz, F, Verier-Mine, O, Perrin, L, Archambeaud, F, Cabrol, S, Rodien, P, Hove, H, Prescott, T, Lacombe, D, Christin-Maitre, S, Touraine, P, Hieronimus, S, Dewailly, D, Young, J, Pugeat, M, Hardelin, J-P & Dodé, C 2014, 'The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients', The Journal of clinical endocrinology and metabolism, bind 99, nr. 10, s. E2138-43. https://doi.org/10.1210/jc.2014-2110

@article{be502b50a1e0432f869ef303ef7c9a4c,

title = "The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients",

abstract = "CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown.OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients.DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7.RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families.CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.",

keywords = "Adolescent, Adult, CHARGE Syndrome, Child, Child, Preschool, DNA Helicases, DNA-Binding Proteins, Family Health, Female, Frameshift Mutation, Genotype, Heterozygote, Humans, Kallmann Syndrome, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Prevalence, Young Adult",

author = "S{\'e}verine Marcos and Julie Sarfati and Chrystel Leroy and Corinne Fouveaut and Philippe Parent and Chantal Metz and Slawomir Wolczynski and Marion G{\'e}rard and Eric Bieth and Fran{\c c}ois Kurtz and Odile Verier-Mine and Laurence Perrin and Fran{\c c}oise Archambeaud and Sylvie Cabrol and Patrice Rodien and Hanne Hove and Trine Prescott and Didier Lacombe and Sophie Christin-Maitre and Philippe Touraine and Sylvie Hieronimus and Didier Dewailly and Jacques Young and Michel Pugeat and Jean-Pierre Hardelin and Catherine Dod{\'e}",

year = "2014",

month = oct,

doi = "10.1210/jc.2014-2110",

language = "English",

volume = "99",

pages = "E2138--43",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "10",

}

TY - JOUR

T1 - The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

AU - Marcos, Séverine

AU - Sarfati, Julie

AU - Leroy, Chrystel

AU - Fouveaut, Corinne

AU - Parent, Philippe

AU - Metz, Chantal

AU - Wolczynski, Slawomir

AU - Gérard, Marion

AU - Bieth, Eric

AU - Kurtz, François

AU - Verier-Mine, Odile

AU - Perrin, Laurence

AU - Archambeaud, Françoise

AU - Cabrol, Sylvie

AU - Rodien, Patrice

AU - Hove, Hanne

AU - Prescott, Trine

AU - Lacombe, Didier

AU - Christin-Maitre, Sophie

AU - Touraine, Philippe

AU - Hieronimus, Sylvie

AU - Dewailly, Didier

AU - Young, Jacques

AU - Pugeat, Michel

AU - Hardelin, Jean-Pierre

AU - Dodé, Catherine

PY - 2014/10

Y1 - 2014/10

N2 - CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown.OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients.DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7.RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families.CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

AB - CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown.OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients.DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7.RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families.CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.

KW - Adolescent

KW - Adult

KW - CHARGE Syndrome

KW - Child

KW - Child, Preschool

KW - DNA Helicases

KW - DNA-Binding Proteins

KW - Family Health

KW - Female

KW - Frameshift Mutation

KW - Genotype

KW - Heterozygote

KW - Humans

KW - Kallmann Syndrome

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Pedigree

KW - Phenotype

KW - Prevalence

KW - Young Adult

U2 - 10.1210/jc.2014-2110

DO - 10.1210/jc.2014-2110

M3 - Journal article

C2 - 25077900

SN - 0021-972X

VL - 99

SP - E2138-43

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 10

ER -

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients

Abstract

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