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

Abstract

Background: The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. Objective: To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. Patients and methods: A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. Results: In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Conclusion: Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

Genomic analysis identifies masqueraders of full‐term cerebral palsy

“…Symptoms of case 5 included intellectual disability and spastic diplegia, which resembled the phenotype of SPG56 38. In cases 6 and 10, we found two known de novo variants in SPAST ,27, 28 which is the most commonly mutated gene (SPG4) in HSP 37. Cases 6 and 10 developed a mild form of spastic diplegia, which was consistent with the severity of other patients who had variants in SPAST .…”

“…This wide range of proportions could be explained by variations in case selection or differences in the criteria used to evaluate pathogenicity. A high rate of pathologic CNVs (16%) was reported in children who were born small for their gestational age (SGA) with a persistent short stature 37. SGA patients enrolled in the previous CP cohorts may have contributed to the higher detection rate of CNVs compared to our CP cohorts, which contained only one SGA patient.…”

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

“…aCGH ( n = 71) or SNP array ( n = 168) were performed according to availability. All experiments were conducted according to the standard protocol of the manufacturer or previously published data [10, 13]. aCGH was performed in a whole-genome 180 K platform (Agilent Technologies, Inc., Santa Clara, CA, USA).…”

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

“…Over 30 different pathogenic CNVs have been described in patients with suspected SRS 15,[51][52][53] . Patients with these CNVs usually have more severe developmental delay and/or intellectual disability than is typically seen in SRS 52,53 .…”