Height matters—from monogenic disorders to normal variation

Durand, Claudia; Rappold, Gudrun

doi:10.1038/nrendo.2012.251

Cited by 46 publications

(37 citation statements)

References 77 publications

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“…Consistent with previous studies, [96][97][98] we find substantial genetic overlap between monogenic and polygenic anthropometric traits, driven primarily by common variants with small effect sizes. Importantly, even though well powered to detect them, we find no evidence of low-frequency variants with strong effect sizes ( Figure 4).…”

Section: Discussionsupporting

confidence: 91%

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Tachmazidou

Süveges

Min

et al. 2017

The American Journal of Human Genetics

147

102

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Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common-and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

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Section: Discussionsupporting

confidence: 91%

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Tachmazidou

Süveges

Min

et al. 2017

The American Journal of Human Genetics

147

102

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“…In addition to providing insight into the constancy of developmental phenotypes, these data may be furthermore relevant to the effects of human SHOX dosage. It is hypothesized that SHOX overexpression leads to tall stature in humans, which is based on the observation that SHOX deletions are dosage sensitive and that people with three or more sex chromosomes (and therefore supernumerary copies of SHOX, as SHOX resides on the pseudoautosomal region of the sex chromosomes) are significantly taller than expected (Durand and Rappold 2013). However, associated with chromosome aneuploidies are changes in hormone levels, which influence the maturation of the growth plate during longitudinal bone growth (Smith et al 1994;Morishima et al 1995), thus confounding interpretations of the cause of tall stature (Ottesen et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…SHOX function in humans is also dosage sensitive; a majority of individuals missing one allele of SHOX have moderately shortened zeugopodal segments, while individuals missing both SHOX alleles have a more penetrant and severe shortening (Rao et al 1997;Belin et al 1998;Shears et al 1998;Zinn et al 2002;Albuisson et al 2012). SHOX duplications have furthermore been hypothesized to lead to tall stature (Ogata et al 2000;Durand and Rappold 2013), highlighting the interest in SHOX dosage and its effect on limb development. Thus, examining the effects of dosage variation is key to understanding the role of Shox and Hox genes in development and disease.…”

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confidence: 99%

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

2014

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The growth and development of the vertebrate limb relies on homeobox genes of the Hox and Shox families, with their independent mutation often giving dose-dependent effects. Here we investigate whether Shox2 and Hox genes function together during mouse limb development by modulating their relative dosage and examining the limb for nonadditive effects on growth. Using double mRNA fluorescence in situ hybridization (FISH) in single embryos, we first show that Shox2 and Hox genes have associated spatial expression dynamics, with Shox2 expression restricted to the proximal limb along with Hoxd9 and Hoxa11 expression, juxtaposing the distal expression of Hoxa13 and Hoxd13. By generating mice with all possible dosage combinations of mutant Shox2 alleles and HoxA/D cluster deletions, we then show that their coordinated proximal limb expression is critical to generate normally proportioned limb segments. These epistatic interactions tune limb length, where Shox2 underexpression enhances, and Shox2 overexpression suppresses, Hox-mutant phenotypes. Disruption of either Shox2 or Hox genes leads to a similar reduction in Runx2 expression in the developing humerus, suggesting their concerted action drives cartilage maturation during normal development. While we furthermore provide evidence that Hox gene function influences Shox2 expression, this regulation is limited in extent and is unlikely on its own to be a major explanation for their genetic interaction. Given the similar effect of human SHOX mutations on regional limb growth, Shox and Hox genes may generally function as genetic interaction partners during the growth and development of the proximal vertebrate limb.T HE vertebrate limb is a valuable model for studying the genetic coordination of a complex developing structure. The proximodistal axis of the limb is composed of discrete segments, the growth and development of which are selectively perturbed when individual, or combinations of, homeobox genes are disrupted. In mice, mutations of the paralogous Hox9 and Hox10 genes result in shortened stylopodal elements (containing the humerus and femur) (FromentalRamain et al. 1996a;Wellik and Capecchi 2003), deletions of Hox11 genes result in truncated zeugopodal elements (radius/ ulna and fibula/tibia) (Davis et al. 1995;Wellik and Capecchi 2003), and disruption of Hox13 genes results in agenesis of the autopod (metacarpals/metatarsals and the digits) (FromentalRamain et al. 1996b). Mutation of short stature homeobox (Shox) genes similarly gives rise to the disproportionate shortening of certain limb regions. In humans, loss of SHOX leads to the truncated zeugopod elements found in people with LeriWeill, Turner, and Langer syndromes (Rao et al. 1997;Belin et al. 1998;Shears et al. 1998;Zinn et al. 2002). While rodents have uniquely lost the Shox gene among mammals (Gianfrancesco et al. 2001), disruption of the widely conserved Shox2 gene results in severely shortened stylopodal elements in mice (Cobb et al. 2006). Thus, Hox and Shox gene perturbations each give ...

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“…The search strategy started with updating information on genetic causes of short stature described in previous reviews (10,11,13) and others (5,14,15,16,17), through OMIM and PubMed. Novel genetic causes were found with the following search strategy (courtesy J. Schoones, Leiden): …”

Section: Search Strategymentioning

confidence: 99%

“…For this review we chose to focus on discoveries made in the last 10 years (up to August 2015), against the background of earlier findings, as summarized in previous reviews by our group (10,11,12,13) and others (5,14,15,16,17) (for search strategy see section at the end of the article). The tables offer the formal names of the disorders and codes according to online Mendelian inheritance in man (OMIM) (http://www.ncbi.nlm.nih.gov/omim), and we aimed at providing the most recent relevant references.…”

Section: Introductionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

153

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Height matters—from monogenic disorders to normal variation

Cited by 46 publications

References 77 publications

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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