Rare Copy Number Variants Are a Common Cause of Short Stature

Abstract

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<1×10−7). 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.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

“…Our results draw attention to the fact that pathogenic and probably pathogenic variants detected occurred in different chromosomal regions, which could explain the clinical variability of the SGA patients investigated in the present study. The same genetic variability was observed in the pathogenic and probably pathogenic CNVs in the two studies mentioned above (12,13). CNVs categorized as pathogenic or probably pathogenic in the present study fulfill some established deleterious criteria.…”

“…In a recent study, underlying pathogenic CNVs have been identified in 20 of 200 patients (10%) with short stature without an apparent cause; eight of these 20 patients were born SGA (13). In another study, genome-wide analysis of CNVs of 162 patients with short stature of unknown origin revealed at least 17 (10.4%) pathogenic variants, regarding familial segregation (12).…”

“…In the field of endocrinology, genome-wide analysis of CNVs has been evaluated as a tool to identify genetic causes in several clinical conditions, including premature ovarian failure (6), severe early-onset obesity (7), congenital hypothyroidism and thyroid dysgenesis (8), ambiguous genitalia (9), skeletal defects with growth impairment (10), and Silver-Russell syndrome (11). Two recent studies have demonstrated the presence of causative and possible pathogenic CNVs in short-stature children (12,13). However, in both studies, children were selected regardless of compromised birth weight and/or length.…”

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Four recent studies (153,215,216,217) showed that w10% of patients with ISS carry a disease-causing CNV, and in short children microdeletions (in contrast to microduplications) are significantly more frequent than in controls (218). However, for individual cases one often remains uncertain whether their growth failure is due to the encountered CNV, and which of the genes is responsible for it.…”

IGF-I Deficiency in the Era of Genomics: Lessons Learned

“…Second, as the authors correctly note, a routine exome analysis does not detect genomic deletions or duplications or methylation abnormalities. Numerous groups have shown that genomic copy number variants (deletions and duplications) underlie a significant portion of patients with severe growth disorders [6,7], and the article by Storr et al [4] suggests that SilverRussell syndrome may be a cause for a number of these patient's short stature. Silver-Russell syndrome is most commonly caused by methylation abnormalities which will not be identified by exome sequencing.…”