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

doi:10.1016/j.heliyon.2023.e23688

Brachyolmia, dental anomalies and short stature (DASS): Phenotype and genotype analyses of Egyptian and Pakistani patients

Heliyon. 2023 Dec 14;10(1):e23688. doi: 10.1016/j.heliyon.2023.e23688. eCollection 2024 Jan 15.

Authors

Hamed Nawaz¹, Asia Parveen^{2

3}, Sher Alam Khan^{1

4}, Abul Khair Zalan⁵, Muhammad Adnan Khan⁶, Noor Muhammad¹, Nehal F Hassib^{7

8}, Mostafa I Mostafa⁷, Rasha M Elhossini⁹, Nehal Nabil Roshdy¹⁰, Asmat Ullah^{11

12}, Amina Arif³, Saadullah Khan¹, Ole Ammerpohl¹³, Naveed Wasif^{13

14}

Affiliations

¹ Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan.
² Department of Biochemistry, Faculty of Life Sciences, Gulab Devi Educational Complex, Gulab Devi Hospital, 54000, Lahore, Pakistan.
³ Faculty of Science and Technology, University of Central Punjab (UCP), Lahore, Pakistan.
⁴ Department of Computer Science and Bioinformatics, Khushal Khan Khatak University, Karak, Pakistan.
⁵ BDS, MDS Registrar Pediatric Dentistry, Department of Pediatric Dentistry, School of Dentistry, PIMS, Islamabad, Pakistan.
⁶ Dental Material, Institute of Basic Medical Sciences, Khyber Medical University Peshawar, Peshawar, Pakistan.
⁷ Orodental Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt.
⁸ School of Dentistry, New Giza University, Giza, Egypt.
⁹ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, 12622, Egypt.
¹⁰ Endodontics, Faculty of Dentistry, Cairo University, Cairo, 11553, Egypt.
¹¹ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹² The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹³ Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany.
¹⁴ Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, D-24105, Kiel, Germany.

Abstract

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.

Keywords: Amelogenesis imperfecta; Brachyolmia; Exome sequencing; Frameshift variants; Hearing impairment; Homozygous splice acceptor site; LTBP3.