Abstract
BackgroundSyndromic 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.MethodsTrio-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.ResultsOf 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.ConclusionsTrio-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.
Highlights
Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes
The online system independently developed by Chigene was used to annotate database-based minor allele frequencies (MAFs) and American College of Medical Genetics (ACMG) practice guideline-based pathogenicity of every yielded gene variant, and the system provides a serial software package for conservative analysis and protein product structure prediction
We identified 2 pathogenic mutations (FGFR3, c.1620C>A p.N540K; TRPS1, c.2527_c.2528dupTA p.S843fsX72) and 1 likely pathogenic mutation (GNAS, c.2288C>T p.A763V) in three patients, respectively
Summary
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. Syndromic short stature is a phenotypic and genetically heterogeneous disease with a complex aetiology, including chromosomal aberrations, copy number variants (CNVs), gene mutations, methylation defects and other unknown causes [1]. Trio-whole exome sequencing (TrioWES) was used to identify pathogenic gene mutations in patients with syndromic short stature of unknown aetiology [7]. The study describes the clinical manifestations, radiological examination and gene mutation analysis findings and rhGH treatment responses in patients with syndromic short stature
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