title: The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: EA7331 Faculté des Sciences Pharmaceutiques (S.M., C.D.), 75006 Paris, France; Laboratoire de Biologie et Génétique Moléculaires (J.S., C.L., C.F., C.D.), Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France; Service de Pédiatrie et de Génétique Médicale (P.P., C.M.), Centre Hospitalier Universitaire Morvan, 29200 Brest, France; Department of Reproduction and Gynecological Endocrinology (S.W.), PL-15-1276 Bialystok, Poland; Service de Génétique (M.G.), Centre Hospitalier Régional Clémenceau, 14033 Caen, France; Service de Génétique Médicale (E.B.), Hôpital Purpan, 31059 Toulouse, France; Service de Pédiatrie (F.K.), Hôpital Bel Air, 57126 Thionville, France; Service d'Edocrinologie (O.V.-M.), Centre Hospitalier, 59322 Valenciennes, France; UF de Génétique Clinique (L.P.), Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, 75019 Paris, France; Service de Médecine et d'Endocrinologie (F.A.), Hôpital du Cluzeau, 87042 Limoges, France; Service d'Endocrinologie (S.C.), Hôpital Trousseau, and Service d'Endocrinologie (S.C.-M.), Hôpital St Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France; Service d'Endocrinologie (P.R.), Centre Hospitalier, 49933 Angers, France; Department of Clinical Genetics (H.H.), University Hospital, DK-1165 Copenhagen, Denmark; Department of Medical Genetics (T.P.), Hospital HF Rikshospital, 0424 Oslo, Norway; Service de Génétique Médicale (D.L.), Hôpital Pellegrin, 33076 Bordeaux, France; Service d'Endocrinologie (P.T.), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France; Service d'Endocrinologie (S.H.), Hôpital l'Archet, 06003 Nice, France; Service de Gynécologie Endocrinienne (D.D.), Hôpital Jeanne de Flandre, 59037 Lille, France; Service d'Endocrinologie (J.Y.), Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin-Bicêtre, France; and Service d'Endocrinologie (M.P.), Hôpital Neurologiqu
authors: Séverine
authors: S
authors: Marcos
authors: Julie
authors: J
authors: Sarfati
authors: Chrystel
authors: C
authors: Leroy
authors: Corinne
authors: C
authors: Fouveaut
authors: Philippe
authors: P
authors: Parent
authors: Chantal
authors: C
authors: Metz
authors: Slawomir
authors: S
authors: Wolczynski
authors: Marion
authors: M
authors: Gérard
authors: Eric
authors: E
authors: Bieth
authors: François
authors: F
authors: Kurtz
authors: Odile
authors: O
authors: Verier-Mine
authors: Laurence
authors: L
authors: Perrin
authors: Françoise
authors: F
authors: Archambeaud
authors: Sylvie
authors: S
authors: Cabrol
authors: Patrice
authors: P
authors: Rodien
authors: Hanne
authors: H
authors: Hove
authors: Trine
authors: T
authors: Prescott
authors: Didier
authors: D
authors: Lacombe
authors: Sophie
authors: S
authors: Christin-Maitre
authors: Philippe
authors: P
authors: Touraine
authors: Sylvie
authors: S
authors: Hieronimus
authors: Didier
authors: D
authors: Dewailly
authors: Jacques
authors: J
authors: Young
authors: Michel
authors: M
authors: Pugeat
authors: Jean-Pierre
authors: JP
authors: Hardelin
authors: Catherine
authors: C
authors: Dodé
mesh_terms: D000293:Adolescent; D000328:Adult; D058747:CHARGE Syndrome / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D017436:Kallmann Syndrome / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human