Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients
Hamed Nawaz,
Asia Parveen,
Sher Alam Khan,
Abul Khair Zalan,
Muhammad Adnan Khan,
Noor Muhammad,
Nehal F. Hassib,
Mostafa I. Mostafa,
Rasha M. Elhossini,
Nehal Nabil Roshdy,
Asmat Ullah,
Amina Arif,
Saadullah Khan,
Ole Ammerpohl,
Naveed Wasif
Affiliations
Hamed Nawaz
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan
Asia Parveen
Department of Biochemistry, Faculty of Life Sciences, Gulab Devi Educational Complex, Gulab Devi Hospital, 54000, Lahore, Pakistan; Faculty of Science and Technology, University of Central Punjab (UCP), Lahore, Pakistan
Sher Alam Khan
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan; Department of Computer Science and Bioinformatics, Khushal Khan Khatak University, Karak, Pakistan
Abul Khair Zalan
BDS, MDS Registrar Pediatric Dentistry, Department of Pediatric Dentistry, School of Dentistry, PIMS, Islamabad, Pakistan
Muhammad Adnan Khan
Dental Material, Institute of Basic Medical Sciences, Khyber Medical University Peshawar, Peshawar, Pakistan
Noor Muhammad
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan
Nehal F. Hassib
Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt; School of Dentistry, New Giza University, Giza, Egypt
Mostafa I. Mostafa
Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
Rasha M. Elhossini
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt
Nehal Nabil Roshdy
Endodontics, Faculty of Dentistry, Cairo University, Cairo, 11553, Egypt
Asmat Ullah
Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Amina Arif
Faculty of Science and Technology, University of Central Punjab (UCP), Lahore, Pakistan
Saadullah Khan
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan; Corresponding author.
Ole Ammerpohl
Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
Naveed Wasif
Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany; Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, D-24105, Kiel, Germany; Corresponding author. Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, D-24105, Kiel, Germany
Brachyolmia is a heterogeneous group of developmental disorders characterized by a short trunk, short stature, scoliosis, and generalized platyspondyly without significant deformities in the long bones. DASS (Dental Abnormalities and Short Stature), caused by alterations in the LTBP3 gene, was previously considered as a subtype of brachyolmia.The present study investigated three unrelated consanguineous families (A, B, C) with Brachyolmia and DASS from Egypt and Pakistan. In our Egyptian patients, we also observed hearing impairment. Exome sequencing was performed to determine the genetic causes of the diverse clinical conditions in the patients. Exome sequencing identified a novel homozygous splice acceptor site variant (LTBP3:c.3629-1G > T; p. ?) responsible for DASS phenotypes and a known homozygous missense variant (CABP2: c.590T > C; p.Ile197Thr) causing hearing impairment in the Egyptian patients. In addition, two previously reported homozygous frameshift variants (LTBP3:c.132delG; p.Pro45Argfs*25) and (LTBP3:c.2216delG; p.Gly739Alafs*7) were identified in Pakistani patients.This study emphasizes the vital role of LTBP3 in the axial skeleton and tooth morphogenesis and expands the mutational spectrum of LTBP3. We are reporting LTBP3 variants in seven patients of three families, majorly causing brachyolmia with dental and cardiac anomalies. Skeletal assessment documented short webbed neck, broad chest, evidences of mild long bones involvement, short distal phalanges, pes planus and osteopenic bone texture as additional associated findings expanding the clinical phenotype of DASS. The current study reveals that the hearing impairment phenotype in Egyptian patients of family A has a separate transmission mechanism independent of LTBP3.
