Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta

Abstract

Whole-exome sequencing (WES) has advantages over the traditional molecular test by screening 20,000 genes simultaneously and has become an invaluable tool for genetic diagnosis in clinical practice. Here, we reported a family with a child and a fetus presenting undiagnosed skeletal dysplasia phenotypes, while the parents were asymptomatic. WES was applied to the parents and affected fetus to identify the genetic cause of the phenotypes. We identified novel compound heterozygous mutations consisting of a single-nucleotide variant (SNV) and a large deletion in the CRTAP gene (NM_006371.4:c.1153-3C > G/hg19 chr3:g.32398837_34210906del). Genetic alterations of CRTAP are known to cause osteogenesis imperfecta (OI) in an autosomal recessive manner. Further examination of the proband's elder sibling who was diagnosed as OI after birth found that she shares the inherited compound heterozygous mutations of CRTAP; thus, the findings support the disease-causing role of CRTAP mutations. Through the in vitro molecular test and in silico analysis, the deleterious effects of the splicing-altering SNV in CRTAP (c.1153-3C > G) on gene product were confirmed. Collectively, our WES-based pathogenic variant discovery pipeline identifies the SNVs and copy number variation to delineate the genetic cause on the proband affected with OI. The data not only extend the knowledge of mutation spectrum in patients with skeletal dysplasia but also demonstrate that WES holds great promise for genetic screening of rare diseases in clinical settings.

Development and validation of an expanded targeted sequencing panel for non-invasive prenatal diagnosis of sporadic skeletal dysplasia

“…No mutation was identified in the cfDNA or in gDNAs from fetal umbilical cord tissue. To investigate the underlying genetic defect of the proband, we performed whole-exome sequencing and found novel compound heterozygous mutations in CRTAP gene consisting of SNV and deletion, suggesting the case was a rare autosomal recessive form of OI [52]. The findings supported the true negative result of cfDNA using the established targeted-seq assay.…”

“…It is of notice that the mutations result in rare autosomal recessive form of severe OI-related symptoms in family 2 [52] were not detected in the established panel. It is still challenging to detect mutations for autosomal recessive diseases in NIPT as the mutations are contributed from both parents thus it may present at various fractions in the mutation sites.…”

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

“…The hydroxylation of these amino acids is crucial for the correct formation of collagen’s triple-helix structure. In the case of type VII, type VIII, and type IX OI, recessive mutations are found in three distinct components encoding the collagen prolyl 3-hydroxylation complexP3H1, CRTAP, and CyPB (encoded by PPIB). ,− These three proteins form a heterotrimeric complex in the ER, facilitating the folding of the triple helix and the PTM of the pre-collagen chain. The primary target of this complex is the modification of the Pro986 residue in collagen.…”

Understanding Musculoskeletal Disorders Through Next-Generation Sequencing

“…Similarly, a P4HB genetic variant was identified using WES, but it needs further validation by additional studies to establish its association with OI 109 . Other genetic variants that have been associated with various forms of OI were identified in potential candidate genes such as COL1A1 110 (OMIM 120150), COL1A2 110 (OMIM 120160), P3H1 (610339), FKBP10 (OMIM 607063), CRTAP 115 (OMIM 605497), and PPIB 116 (OMIM 123841).…”