Targeted Resequencing of the Pericentromere of Chromosome 2 Linked to Constitutional Delay of Growth and Puberty

Show simple item record Cousminer, Diana L. Leinonen, Jaakko T. Sarin, Antti-Pekka Chheda, Himanshu Surakka, Ida Wehkalampi, Karoliina Ellonen, Pekka Ripatti, Samuli Dunkel, Leo Palotie, Aarno Widen, Elisabeth 2015-08-31T11:40:01Z 2015-08-31T11:40:01Z 2015-06-01
dc.identifier.citation Cousminer , D L , Leinonen , J T , Sarin , A-P , Chheda , H , Surakka , I , Wehkalampi , K , Ellonen , P , Ripatti , S , Dunkel , L , Palotie , A & Widen , E 2015 , ' Targeted Resequencing of the Pericentromere of Chromosome 2 Linked to Constitutional Delay of Growth and Puberty ' , PLoS One , vol. 10 , no. 6 , 0128524 .
dc.identifier.other PURE: 52193454
dc.identifier.other PURE UUID: 5cc1ad53-4a17-4175-9d2f-77755e05e3d3
dc.identifier.other WOS: 000356630900164
dc.identifier.other Scopus: 84932619650
dc.identifier.other ORCID: /0000-0001-6072-0489/work/52863085
dc.identifier.other ORCID: /0000-0002-2527-5874/work/97266359
dc.description.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. en
dc.format.extent 16
dc.language.iso eng
dc.relation.ispartof PLoS One
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject FINAL HEIGHT
dc.subject LOCI
dc.subject GIRLS
dc.subject POPULATION
dc.subject VARIANTS
dc.subject BOYS
dc.subject DISORDERS
dc.subject MUTATIONS
dc.subject PATTERNS
dc.subject 3111 Biomedicine
dc.title Targeted Resequencing of the Pericentromere of Chromosome 2 Linked to Constitutional Delay of Growth and Puberty en
dc.type Article
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Children's Hospital
dc.contributor.organization Clinicum
dc.contributor.organization Samuli Olli Ripatti / Principal Investigator
dc.contributor.organization Department of Public Health
dc.contributor.organization Aarno Palotie / Principal Investigator
dc.contributor.organization Elisabeth Ingrid Maria Widen / Principal Investigator
dc.contributor.organization Biostatistics Helsinki
dc.contributor.organization Complex Disease Genetics
dc.contributor.organization Genomics of Neurological and Neuropsychiatric Disorders
dc.contributor.organization Genomic Discoveries and Clinical Translation
dc.description.reviewstatus Peer reviewed
dc.relation.issn 1932-6203
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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