Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study

Abstract

Background/Aims: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. Methods: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. Results: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson’s χ² test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. Conclusion: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm.

Analysis of Prevalence, Influencing Factors, and Countermeasures of Short Stature in Children and Adolescents Aged 6∼14 in Furong District, Changsha City, in 2020

“…Full-term infants with body weight less than 2,500 g or birth length less than 47 cm are defined as having intrauterine growth retardation. Studies suggest that the population which has growth-related endocrine abnormalities and insensitivity to growth hormone has a much higher chance of developing short stature in childhood than in normal population [ 19 ].…”

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

“…Synonymous variants were not considered. Following their respective analysis pipelines, 15 , 16 , 17 , 18 participating centers generated a list of candidate variants filtered against variants from public databases according to modes of inheritance, then compared their results through international research networks and variant databases. 19 , 20 …”

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

“…[25][26][27][28] Current studies assessing diagnostic yield of exome sequencing for syndromic short stature with prior negative karyotype, microarray and NGS targeted panels is reported between 16.5% and 46%. [29][30][31][32] Clinical genome sequencing has begun to be offered in select laboratories and can be considered if available. At this time, important considerations include the cost of this testing, insurance reimbursement, and lack of evidence that clinical genome sequencing has a significantly increased diagnostic yield compared with clinical exome sequencing.…”