Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature

Nadine N Hauer, Bernt Popp, Leila Taher, Carina Vogl, Perundurai S Dhandapany, Christian Büttner, Steffen Uebe, Heinrich Sticht, Fulvia Ferrazzi, Arif B Ekici, Alessandro De Luca, Patrizia Klinger, Cornelia Kraus, Christiane Zweier, Antje Wiesener, Rami Abou Jamra, Erdmute Kunstmann, Anita Rauch, Dagmar Wieczorek, Anna-Marie Jung & 5 Sonstige Tilman R Rohrer, Martin Zenker, Helmuth-Guenther Doerr, André Reis, Christian T Thiel

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

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.

Originalspracheenglisch
Seiten (von - bis)1061-1071
Seitenumfang11
FachzeitschriftEuropean Journal of Human Genetics
Jahrgang27
Ausgabenummer7
DOIs
PublikationsstatusVeröffentlicht - Jul 2019

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Genes
Growth
Exome
Chondrocytes
Population
Ciliopathies

Fields of Expertise

  • Human- & Biotechnology

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Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature. / Hauer, Nadine N; Popp, Bernt; Taher, Leila; Vogl, Carina; Dhandapany, Perundurai S; Büttner, Christian; Uebe, Steffen; Sticht, Heinrich; Ferrazzi, Fulvia; Ekici, Arif B; De Luca, Alessandro; Klinger, Patrizia; Kraus, Cornelia; Zweier, Christiane; Wiesener, Antje; Jamra, Rami Abou; Kunstmann, Erdmute; Rauch, Anita; Wieczorek, Dagmar; Jung, Anna-Marie; Rohrer, Tilman R; Zenker, Martin; Doerr, Helmuth-Guenther; Reis, André; Thiel, Christian T.

in: European Journal of Human Genetics , Jahrgang 27, Nr. 7, 07.2019, S. 1061-1071.

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Hauer, NN, Popp, B, Taher, L, Vogl, C, Dhandapany, PS, Büttner, C, Uebe, S, Sticht, H, Ferrazzi, F, Ekici, AB, De Luca, A, Klinger, P, Kraus, C, Zweier, C, Wiesener, A, Jamra, RA, Kunstmann, E, Rauch, A, Wieczorek, D, Jung, A-M, Rohrer, TR, Zenker, M, Doerr, H-G, Reis, A & Thiel, CT 2019, 'Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature' European Journal of Human Genetics , Jg. 27, Nr. 7, S. 1061-1071. https://doi.org/10.1038/s41431-019-0362-0
Hauer, Nadine N ; Popp, Bernt ; Taher, Leila ; Vogl, Carina ; Dhandapany, Perundurai S ; Büttner, Christian ; Uebe, Steffen ; Sticht, Heinrich ; Ferrazzi, Fulvia ; Ekici, Arif B ; De Luca, Alessandro ; Klinger, Patrizia ; Kraus, Cornelia ; Zweier, Christiane ; Wiesener, Antje ; Jamra, Rami Abou ; Kunstmann, Erdmute ; Rauch, Anita ; Wieczorek, Dagmar ; Jung, Anna-Marie ; Rohrer, Tilman R ; Zenker, Martin ; Doerr, Helmuth-Guenther ; Reis, André ; Thiel, Christian T. / Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature. in: European Journal of Human Genetics . 2019 ; Jahrgang 27, Nr. 7. S. 1061-1071.
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abstract = "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.",
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AU - Hauer, Nadine N

AU - Popp, Bernt

AU - Taher, Leila

AU - Vogl, Carina

AU - Dhandapany, Perundurai S

AU - Büttner, Christian

AU - Uebe, Steffen

AU - Sticht, Heinrich

AU - Ferrazzi, Fulvia

AU - Ekici, Arif B

AU - De Luca, Alessandro

AU - Klinger, Patrizia

AU - Kraus, Cornelia

AU - Zweier, Christiane

AU - Wiesener, Antje

AU - Jamra, Rami Abou

AU - Kunstmann, Erdmute

AU - Rauch, Anita

AU - Wieczorek, Dagmar

AU - Jung, Anna-Marie

AU - Rohrer, Tilman R

AU - Zenker, Martin

AU - Doerr, Helmuth-Guenther

AU - Reis, André

AU - Thiel, Christian T

PY - 2019/7

Y1 - 2019/7

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.

AB - 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.

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DO - 10.1038/s41431-019-0362-0

M3 - Article

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JF - European Journal of Human Genetics

SN - 1018-4813

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