A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family
(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the <i>DYM</i> gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dy...
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MDPI AG
2023-02-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/2/510 |
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| author | Abu Bakar Sulaiman Shams Nousheen Bibi Asmat Ullah Wasim Ahmad Musharraf Jelani Osama Yousef Muthaffar Angham Abdulrhman Abdulkareem Turki S. Abujamel Absarul Haque Muhammad Imran Naseer Bushra Khan |
| author_facet | Abu Bakar Sulaiman Shams Nousheen Bibi Asmat Ullah Wasim Ahmad Musharraf Jelani Osama Yousef Muthaffar Angham Abdulrhman Abdulkareem Turki S. Abujamel Absarul Haque Muhammad Imran Naseer Bushra Khan |
| author_sort | Abu Bakar |
| collection | DOAJ |
| description | (1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the <i>DYM</i> gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In the present study, large consanguineous families with five affected individuals with osteochondrodysplasia phenotypes were recruited. The family members were analyzed by polymerase chain reaction for homozygosity mapping using highly polymorphic microsatellite markers. Subsequent to linkage analysis, the coding exons and exon intron border of the <i>DYM</i> gene were amplified. The amplified products were then sent for Sanger sequencing. The structural effect of the pathogenic variant was analyzed by different bioinformatics tools. (3) Results: Homozygosity mapping revealed a 9 Mb homozygous region on chromosome 18q21.1 harboring <i>DYM</i> shared by all available affected individuals. Sanger sequencing of the coding exons and exon intron borders of the <i>DYM</i> gene revealed a novel homozygous nonsense variant [DYM (NM_017653.6):c.1205T>A, p.(Leu402Ter)] in affected individuals. All the available unaffected individuals were either heterozygous or wild type for the identified variant. The identified mutation results in loss of protein stability and weekend interactions with other proteins making them pathogenic (4) Conclusions: This is the second nonsense mutation reported in a Pakistani population causing DMC. The study presented would be helpful in prenatal screening, genetic counseling, and carrier testing of other members in the Pakistani community. |
| first_indexed | 2024-03-11T08:46:41Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T08:46:41Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-2f4d1530a28c4038ad578f8ea0d43f5b2023-11-16T20:43:58ZengMDPI AGGenes2073-44252023-02-0114251010.3390/genes14020510A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous FamilyAbu Bakar0Sulaiman Shams1Nousheen Bibi2Asmat Ullah3Wasim Ahmad4Musharraf Jelani5Osama Yousef Muthaffar6Angham Abdulrhman Abdulkareem7Turki S. Abujamel8Absarul Haque9Muhammad Imran Naseer10Bushra Khan11Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, PakistanDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, PakistanDepartment of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar 25120, PakistanNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, DenmarkDepartment of Biochemistry, Quaid-I-Azam University, Islamabad 45320, PakistanRare Diseases Genetics and Genomics, Centre for Omic Sciences, Islamia College Peshawar, Peshawar 25120, PakistanDepartment of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi ArabiaFaculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi ArabiaCenter of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan(1) Background: Dyggve-Melchior-Clausen Syndrome is a skeletal dysplasia caused by a defect in the <i>DYM</i> gene (OMIM number 607461). Pathogenic variants in the gene have been reported to cause Dyggve-Melchior-Clausen (DMC; OMIM 223800) dysplasia and Smith-McCort (SMC; OMIM 607326) dysplasia. (2) Methods: In the present study, large consanguineous families with five affected individuals with osteochondrodysplasia phenotypes were recruited. The family members were analyzed by polymerase chain reaction for homozygosity mapping using highly polymorphic microsatellite markers. Subsequent to linkage analysis, the coding exons and exon intron border of the <i>DYM</i> gene were amplified. The amplified products were then sent for Sanger sequencing. The structural effect of the pathogenic variant was analyzed by different bioinformatics tools. (3) Results: Homozygosity mapping revealed a 9 Mb homozygous region on chromosome 18q21.1 harboring <i>DYM</i> shared by all available affected individuals. Sanger sequencing of the coding exons and exon intron borders of the <i>DYM</i> gene revealed a novel homozygous nonsense variant [DYM (NM_017653.6):c.1205T>A, p.(Leu402Ter)] in affected individuals. All the available unaffected individuals were either heterozygous or wild type for the identified variant. The identified mutation results in loss of protein stability and weekend interactions with other proteins making them pathogenic (4) Conclusions: This is the second nonsense mutation reported in a Pakistani population causing DMC. The study presented would be helpful in prenatal screening, genetic counseling, and carrier testing of other members in the Pakistani community.https://www.mdpi.com/2073-4425/14/2/510<i>DYM</i> geneDyggve-Melchior-Clausen Syndromehomozgosity mappingsanger sequencingnovel homozygousnon-sense variant |
| spellingShingle | Abu Bakar Sulaiman Shams Nousheen Bibi Asmat Ullah Wasim Ahmad Musharraf Jelani Osama Yousef Muthaffar Angham Abdulrhman Abdulkareem Turki S. Abujamel Absarul Haque Muhammad Imran Naseer Bushra Khan A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family Genes <i>DYM</i> gene Dyggve-Melchior-Clausen Syndrome homozgosity mapping sanger sequencing novel homozygous non-sense variant |
| title | A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family |
| title_full | A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family |
| title_fullStr | A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family |
| title_full_unstemmed | A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family |
| title_short | A Novel Homozygous Nonsense Variant in the <i>DYM</i> Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family |
| title_sort | novel homozygous nonsense variant in the i dym i underlies dyggve melchior clausen syndrome in large consanguineous family |
| topic | <i>DYM</i> gene Dyggve-Melchior-Clausen Syndrome homozgosity mapping sanger sequencing novel homozygous non-sense variant |
| url | https://www.mdpi.com/2073-4425/14/2/510 |
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