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Exome-Wide Copy Number Variation Analysis Identifies a Col9a1 in Frame Deletion That Is Associated With Hearing Loss Publisher Pubmed



Hofrichter MAH1 ; Doll J1 ; Habibi H2 ; Enayati S3 ; Vahidi Mehrjardi MY4, 5 ; Muller T6 ; Dittrich M1, 6 ; Haaf T1 ; Vona B1, 7
Authors
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Authors Affiliations
  1. 1. Institute of Human Genetics, Julius Maximilians University, Wurzburg, Germany
  2. 2. Genetic Counselling Center, Hamadan University of Medical Science, Daneshgah-e-Bu Ali Sina, Hamedan, Iran
  3. 3. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Medical Genetics Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  5. 5. Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
  6. 6. Institute of Bioinformatics, Julius Maximilians University, Wurzburg, Germany
  7. 7. Department of Otorhinolaryngology-Head and Neck Surgery, Tubingen Hearing Research Centre, Eberhard Karls University Tubingen, Tubingen, Germany

Source: European Journal of Medical Genetics Published:2019


Abstract

Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697–3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL. © 2019 The Authors
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