TY  - JOUR
A1  - Hauer, Nadine N.
A1  - Popp, Bernt
A1  - Taher, Leila
A1  - Vogl, Carina
A1  - Dhandapany, Perundurai S.
A1  - Büttner, Christian
A1  - Uebe, Steffen
A1  - Sticht, Heinrich
A1  - Ferrazzi, Fulvia
A1  - Ekici, Arif B.
A1  - De Luca, Alessandro
A1  - Klinger, Patrizia
A1  - Kraus, Cornelia
A1  - Zweier, Christiane
A1  - Wiesener, Antje
A1  - Abou Jamra, Rami
A1  - Kunstmann, Erdmute
A1  - Rauch, Anita
A1  - Wieczorek, Dagmar
A1  - Jung, Anna-Marie
A1  - Rohrer, Tilman R.
A1  - Zenker, Martin
A1  - Doerr, Helmuth-Guenther
A1  - Reis, André
A1  - Thiel, Christian T.
T1  - Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature
JF  - European Journal of Human Genetics
N2  - Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.
KW  - disease genetics
KW  - DNA sequencing
KW  - genetic counselling
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227899
VL  - 27
ER  - 
TY  - JOUR
A1  - Zahnleiter, Diana
A1  - Uebe, Steffen
A1  - Ekici, Arif B.
A1  - Hoyer, Juliane
A1  - Wiesener, Antje
A1  - Wieczorek, Dagmar
A1  - Kunstmann, Erdmute
A1  - Reis, André
A1  - Doerr, Helmuth-Guenther
A1  - Rauch, Anita
A1  - Thiel, Christian T.
T1  - Rare Copy Number Variants Are a Common Cause of Short Stature
JF  - PLoS Genetics
N2  - Human growth has an estimated heritability of about 80%-90%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs \((p-value <1 x 10^{-7})\). In a gene-based analysis of all non-polymorphic CNVs >50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p < 0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p < 0.01). Eleven (55%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation.
KW  - genetic skeletal disorders
KW  - microdeletion syndrome
KW  - mental retardation
KW  - growth failure
KW  - deletion
KW  - classification
KW  - association
KW  - mutations
KW  - genome
KW  - abnormalities
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127645
SN  - 1553-7404
VL  - 9
IS  - 3
ER  -