CONTEXT: Twin studies indicate that the timing of pubertal onset is under strong genetic control. However, genes controlling pubertal timing in the general population have not yet been identified. OBJECTIVE: To facilitate the identification of genes influencing the timing of pubertal growth and maturation, we conducted linkage mapping of constitutional delay of growth and puberty (CDGP), an extreme variant of normal pubertal timing, in extended families. PARTICIPANTS AND METHODS: Fifty-two families multiply affected with CDGP were genotyped with 383 multiallelic markers. CDGP was defined based on growth charts (the age at onset of growth spurt, peak height velocity, or attaining adult height taking place at least 1.5 sd later than average). Chromosomal regions cosegregating with CDGP were identified with parametric affected-only linkage analysis using CDGP as a dichotomized trait. RESULTS: The genome-wide scan detected linkage of CDGP to a region on chromosome 2p13-2q13. The two-point heterogeneity LOD (HLOD) score was 1.62 (alpha = 0.27), and the corresponding multipoint HLOD was 2.54 (alpha = 0.31). Fine-mapping the region at 1 cM resolution increased the multipoint HLOD score to 4.44 (alpha = 0.41). The linkage became weaker if family members diagnosed with CDGP without growth data were also included in the analyses. CONCLUSIONS: The pericentromeric region of chromosome 2 harbors a gene predisposing to pubertal delay in multiply affected pedigrees. Our data suggest that this locus may be a component of the internal clock controlling the timing of the onset of puberty.
CONTEXT: Twin studies indicate that the timing of pubertal onset is under strong genetic control. However, genes controlling pubertal timing in the general population have not yet been identified. OBJECTIVE: To facilitate the identification of genes influencing the timing of pubertal growth and maturation, we conducted linkage mapping of constitutional delay of growth and puberty (CDGP), an extreme variant of normal pubertal timing, in extended families. PARTICIPANTS AND METHODS: Fifty-two families multiply affected with CDGP were genotyped with 383 multiallelic markers. CDGP was defined based on growth charts (the age at onset of growth spurt, peak height velocity, or attaining adult height taking place at least 1.5 sd later than average). Chromosomal regions cosegregating with CDGP were identified with parametric affected-only linkage analysis using CDGP as a dichotomized trait. RESULTS: The genome-wide scan detected linkage of CDGP to a region on chromosome 2p13-2q13. The two-point heterogeneity LOD (HLOD) score was 1.62 (alpha = 0.27), and the corresponding multipoint HLOD was 2.54 (alpha = 0.31). Fine-mapping the region at 1 cM resolution increased the multipoint HLOD score to 4.44 (alpha = 0.41). The linkage became weaker if family members diagnosed with CDGP without growth data were also included in the analyses. CONCLUSIONS: The pericentromeric region of chromosome 2 harbors a gene predisposing to pubertal delay in multiply affected pedigrees. Our data suggest that this locus may be a component of the internal clock controlling the timing of the onset of puberty.
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Authors: Sasha R Howard; Leonardo Guasti; Gerard Ruiz-Babot; Alessandra Mancini; Alessia David; Helen L Storr; Lousie A Metherell; Michael Je Sternberg; Claudia P Cabrera; Helen R Warren; Michael R Barnes; Richard Quinton; Nicolas de Roux; Jacques Young; Anne Guiochon-Mantel; Karoliina Wehkalampi; Valentina André; Yoav Gothilf; Anna Cariboni; Leo Dunkel Journal: EMBO Mol Med Date: 2016-06-01 Impact factor: 12.137
Authors: Daniele Cassatella; Sasha R Howard; James S Acierno; Cheng Xu; Georgios E Papadakis; Federico A Santoni; Andrew A Dwyer; Sara Santini; Gerasimos P Sykiotis; Caroline Chambion; Jenny Meylan; Laura Marino; Lucie Favre; Jiankang Li; Xuanzhu Liu; Jianguo Zhang; Pierre-Marc Bouloux; Christian De Geyter; Anne De Paepe; Waljit S Dhillo; Jean-Marc Ferrara; Michael Hauschild; Mariarosaria Lang-Muritano; Johannes R Lemke; Christa Flück; Attila Nemeth; Franziska Phan-Hug; Duarte Pignatelli; Vera Popovic; Sandra Pekic; Richard Quinton; Gabor Szinnai; Dagmar l'Allemand; Daniel Konrad; Saba Sharif; Özlem Turhan Iyidir; Brian J Stevenson; Huanming Yang; Leo Dunkel; Nelly Pitteloud Journal: Eur J Endocrinol Date: 2018-02-01 Impact factor: 6.664
Authors: Sasha R Howard; Roberto Oleari; Ariel Poliandri; Vasiliki Chantzara; Alessandro Fantin; Gerard Ruiz-Babot; Louise A Metherell; Claudia P Cabrera; Michael R Barnes; Karoliina Wehkalampi; Leonardo Guasti; Christiana Ruhrberg; Anna Cariboni; Leo Dunkel Journal: J Clin Endocrinol Metab Date: 2018-09-01 Impact factor: 5.958