Molecular genetic analysis and growth hormone response in patients with syndromic short stature

Abstract Background Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response. Methods Trio-whole-exome...

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Autores principales:	Huihui Sun, Na Li, Naijun Wan
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Syndromic short stature Trio-whole-exome sequencing Whole-genome low-coverage sequencing FGFR3 GNAS TRPS1 Internal medicine RC31-1245 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/d945622b306c4bcbba694ed92c48f9a9
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spelling	oai:doaj.org-article:d945622b306c4bcbba694ed92c48f9a92021-11-07T12:06:42ZMolecular genetic analysis and growth hormone response in patients with syndromic short stature10.1186/s12920-021-01113-81755-8794https://doaj.org/article/d945622b306c4bcbba694ed92c48f9a92021-11-01T00:00:00Zhttps://doi.org/10.1186/s12920-021-01113-8https://doaj.org/toc/1755-8794Abstract Background Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response. Methods Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature. Results Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [− 5.05 standard deviation (SD)] to 100.4 cm (− 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (− 2.69 SD) to 145.0 cm (− 2.36 SD), and her increased height SDS was 0.33. Conclusions Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.Huihui SunNa LiNaijun WanBMCarticleSyndromic short statureTrio-whole-exome sequencingWhole-genome low-coverage sequencingFGFR3GNASTRPS1Internal medicineRC31-1245GeneticsQH426-470ENBMC Medical Genomics, Vol 14, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Syndromic short stature Trio-whole-exome sequencing Whole-genome low-coverage sequencing FGFR3 GNAS TRPS1 Internal medicine RC31-1245 Genetics QH426-470
spellingShingle	Syndromic short stature Trio-whole-exome sequencing Whole-genome low-coverage sequencing FGFR3 GNAS TRPS1 Internal medicine RC31-1245 Genetics QH426-470 Huihui Sun Na Li Naijun Wan Molecular genetic analysis and growth hormone response in patients with syndromic short stature
description	Abstract Background Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response. Methods Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature. Results Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [− 5.05 standard deviation (SD)] to 100.4 cm (− 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (− 2.69 SD) to 145.0 cm (− 2.36 SD), and her increased height SDS was 0.33. Conclusions Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.
format	article
author	Huihui Sun Na Li Naijun Wan
author_facet	Huihui Sun Na Li Naijun Wan
author_sort	Huihui Sun
title	Molecular genetic analysis and growth hormone response in patients with syndromic short stature
title_short	Molecular genetic analysis and growth hormone response in patients with syndromic short stature
title_full	Molecular genetic analysis and growth hormone response in patients with syndromic short stature
title_fullStr	Molecular genetic analysis and growth hormone response in patients with syndromic short stature
title_full_unstemmed	Molecular genetic analysis and growth hormone response in patients with syndromic short stature
title_sort	molecular genetic analysis and growth hormone response in patients with syndromic short stature
publisher	BMC
publishDate	2021
url	https://doaj.org/article/d945622b306c4bcbba694ed92c48f9a9
work_keys_str_mv	AT huihuisun moleculargeneticanalysisandgrowthhormoneresponseinpatientswithsyndromicshortstature AT nali moleculargeneticanalysisandgrowthhormoneresponseinpatientswithsyndromicshortstature AT naijunwan moleculargeneticanalysisandgrowthhormoneresponseinpatientswithsyndromicshortstature
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Molecular genetic analysis and growth hormone response in patients with syndromic short stature

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