Sher Alam Khan1, Ayesha Rukan2, Asmat Ullah3, Nousheen Bibi4, Muhammad Humayun1, Wasim Ullah1, Rubab Raza5, Noor Muhammad1, Wasim Ahmad5, Saadullah Khan1, Umm E-Kalsoom2. 1. Department of Biotechnology & Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan. 2. Department of Biochemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan. 3. Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan. 4. Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan. 5. Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
Abstract
BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a congenital anomaly characterized by hypohydrosis, hypotrichosis and hypodontia. Mutations in at least four genes (EDAR, EDARADD, WNT10A, TRAF6) have been reported to cause both autosomal recessive and autosomal dominant forms of HED. Mutations in two other genes (EDA and IKBKG) have been reported to cause X-linked HED. OBJECTIVES: To clinically characterize three consanguineous families (A-C) segregating with autosomal recessive HED and identify possible disease-causing variants of EDAR and EDARADD genes. MATERIALS AND METHODS: The genes, EDAR and EDARADD, were sequenced in Family A and C, and exome sequencing was performed in Family B. Additionally, in Family A and C, the effect of the identified variants was examined by analysis of EDAR mRNA, extracted from hair follicles from both affected and unaffected members. RESULTS: Sequence analysis revealed three possible disease-causing EDAR variants including a novel splice acceptor site variant (IVS3-1G > A) in Family A and two previously reported mutations (p.[Ala26Val], p.[Arg25*]) in the two other families. Previously, the nonsense variant p.(Arg25*) was reported only in the heterozygous state. Analysis of the RNA, extracted from hair follicles, revealed skipping of a downstream exon in EDAR and complete degradation of EDAR mRNA in affected members in family A and C, respectively. Computational modelling validated the pathogenic effect of the two variants identified in Family B and C. CONCLUSION: The three variants reported here expand the spectrum of EDAR mutations associated with HED which may further facilitate genetic counselling of families segregating with similar disorders in the Pakistani population.
BACKGROUND:Hypohidrotic ectodermal dysplasia (HED) is a congenital anomaly characterized by hypohydrosis, hypotrichosis and hypodontia. Mutations in at least four genes (EDAR, EDARADD, WNT10A, TRAF6) have been reported to cause both autosomal recessive and autosomal dominant forms of HED. Mutations in two other genes (EDA and IKBKG) have been reported to cause X-linked HED. OBJECTIVES: To clinically characterize three consanguineous families (A-C) segregating with autosomal recessive HED and identify possible disease-causing variants of EDAR and EDARADD genes. MATERIALS AND METHODS: The genes, EDAR and EDARADD, were sequenced in Family A and C, and exome sequencing was performed in Family B. Additionally, in Family A and C, the effect of the identified variants was examined by analysis of EDAR mRNA, extracted from hair follicles from both affected and unaffected members. RESULTS: Sequence analysis revealed three possible disease-causing EDAR variants including a novel splice acceptor site variant (IVS3-1G > A) in Family A and two previously reported mutations (p.[Ala26Val], p.[Arg25*]) in the two other families. Previously, the nonsense variant p.(Arg25*) was reported only in the heterozygous state. Analysis of the RNA, extracted from hair follicles, revealed skipping of a downstream exon in EDAR and complete degradation of EDAR mRNA in affected members in family A and C, respectively. Computational modelling validated the pathogenic effect of the two variants identified in Family B and C. CONCLUSION: The three variants reported here expand the spectrum of EDAR mutations associated with HED which may further facilitate genetic counselling of families segregating with similar disorders in the Pakistani population.
Authors: Sher Alam Khan; Saadullah Khan; Noor Muhammad; Zia Ur Rehman; Muhammad Adnan Khan; Abdul Nasir; Umm-E- Kalsoom; Anwar Kamal Khan; Hassan Khan; Naveed Wasif Journal: Front Genet Date: 2022-01-25 Impact factor: 4.599