title: Targeted resequencing of the pericentromere of chromosome 2 linked to constitutional delay of growth and puberty.
abstract: Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Cousminer
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko T
authors.initials: JT
authors.lastname: Leinonen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Chheda
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.affiliation: Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Karoliina
authors.initials: K
authors.lastname: Wehkalampi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; The Medical and Population Genomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widén
mesh_terms: D000293:Adolescent; D002503:Centromere; D002889:Chromosomes, Human, Pair 2; D059472:Exome; D005260:Female; D015894:Genome, Human; D006128:Growth / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D011627:Puberty / Q000235:genetics*; D017422:Sequence Analysis, DNA