María Carmen Martínez-Romero1,2, María Juliana Ballesta-Martínez3,4, Vanesa López-González3,4, María José Sánchez-Soler3,4, Ana Teresa Serrano-Antón3, María Barreda-Sánchez4, Lidya Rodriguez-Peña3, María Teresa Martínez-Menchon5, José Frías-Iniesta5, Paloma Sánchez-Pedreño5, Pablo Carbonell-Meseguer1, Guillermo Glover-López1, Encarna Guillén-Navarro6,7. 1. Centro de Bioquímica y Genética Clínica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB- Arrixaca. Murcia. CIBERER-ISCIII, Madrid, Spain. 2. Programa de doctorado en Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain. 3. Sección Genética Médica. Servicio de Pediatría. Hospital Clínico Universitario Virgen de la Arrixaca. IMIB- Arrixaca, Universidad de Murcia. CIBERER-ISCIII, Madrid, Spain. 4. Cátedra de Genética. Facultad de Ciencias de la Salud, Universidad Católica de Murcia (UCAM), Murcia, Spain. 5. Servicio de Dermatología. Hospital Clínico Universitario Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain. 6. Departamento de Cirugía, Pediatría, Obstetricia y Ginecología. Facultad de Medicina, Universidad de Murcia, Murcia, Spain. encarna.guillen@carm.es. 7. Sección Genética Médica (Hospital Materno-Infantil. Planta 0), Hospital Clínico Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena s/n, El Palmar, CP 30120, Murcia, Spain. encarna.guillen@carm.es.
Abstract
BACKGROUND: Ectodermal dysplasias (ED) are a group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives. An attenuated phenotype is considered a non-syndromic trait when the patient is affected by only one impaired ectodermal structure, such as in non-syndromic tooth agenesis (NSTA) disorder. Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common subtype, with an incidence of 1/50,000-100,000 males, and is associated with the EDA gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (2q13) and EDARADD (1q42.3) genes, respectively. The WNT10A gene (2q35) is associated more frequently with NSTA. Our goal was to determine the mutational spectrum in a cohort of 72 Spanish patients affected by one or more ectodermal derivative impairments referred to as HED (63/72) or NSTA (9 /72) to establish the prevalence of the allelic variants of the four most frequently associated genes. Sanger sequencing of the EDA, EDAR, EDARADD and WNT10A genes and multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: A total of 61 children and 11 adults, comprising 50 males and 22 females, were included. The average ages were 5.4 and 40.2 years for children and adults, respectively. A molecular basis was identified in 51/72 patients, including 47/63 HED patients, for whom EDA was the most frequently involved gene, and 4/9 NSTA patients, most of whom had variants of WNT10A. Among all the patients, 37/51 had variants of EDA, 8/51 had variants of the WNT10A gene, 4/51 had variants of EDAR and 5/51 had variants of EDARADD. In 42/51 of cases, the variants were inherited according to an X-linked pattern (27/42), with the remaining showing an autosomal dominant (10/42) or autosomal recessive (5/42) pattern. Among the NSTA patients, 3/9 carried pathogenic variants of WNT10A and 1/9 carried EDA variants. A total of 60 variants were detected in 51 patients, 46 of which were different, and out of these 46 variants, 12 were novel. CONCLUSIONS: This is the only molecular study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in HED and 44.4% in NSTA. Twelve novel variants were identified. The WNT10A gene has been confirmed as the second molecular candidate that has been identified and accounts for one-half of non-EDA patients and one-third of NSTA patients. Further studies using next generation sequencing (NGS) will help to identify other contributory genes in the remaining uncharacterized Spanish patients.
BACKGROUND:Ectodermal dysplasias (ED) are a group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives. An attenuated phenotype is considered a non-syndromic trait when the patient is affected by only one impaired ectodermal structure, such as in non-syndromic tooth agenesis (NSTA) disorder. Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common subtype, with an incidence of 1/50,000-100,000 males, and is associated with the EDA gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (2q13) and EDARADD (1q42.3) genes, respectively. The WNT10A gene (2q35) is associated more frequently with NSTA. Our goal was to determine the mutational spectrum in a cohort of 72 Spanish patients affected by one or more ectodermal derivative impairments referred to as HED (63/72) or NSTA (9 /72) to establish the prevalence of the allelic variants of the four most frequently associated genes. Sanger sequencing of the EDA, EDAR, EDARADD and WNT10A genes and multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: A total of 61 children and 11 adults, comprising 50 males and 22 females, were included. The average ages were 5.4 and 40.2 years for children and adults, respectively. A molecular basis was identified in 51/72 patients, including 47/63 HEDpatients, for whom EDA was the most frequently involved gene, and 4/9 NSTApatients, most of whom had variants of WNT10A. Among all the patients, 37/51 had variants of EDA, 8/51 had variants of the WNT10A gene, 4/51 had variants of EDAR and 5/51 had variants of EDARADD. In 42/51 of cases, the variants were inherited according to an X-linked pattern (27/42), with the remaining showing an autosomal dominant (10/42) or autosomal recessive (5/42) pattern. Among the NSTApatients, 3/9 carried pathogenic variants of WNT10A and 1/9 carried EDA variants. A total of 60 variants were detected in 51 patients, 46 of which were different, and out of these 46 variants, 12 were novel. CONCLUSIONS: This is the only molecular study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in HED and 44.4% in NSTA. Twelve novel variants were identified. The WNT10A gene has been confirmed as the second molecular candidate that has been identified and accounts for one-half of non-EDApatients and one-third of NSTApatients. Further studies using next generation sequencing (NGS) will help to identify other contributory genes in the remaining uncharacterized Spanish patients.
Authors: Nikhil Shri Sahajpal; Chi-Yu Jill Lai; Alex Hastie; Ashis K Mondal; Siavash Raeisi Dehkordi; Caspar I van der Made; Olivier Fedrigo; Farooq Al-Ajli; Sawan Jalnapurkar; Marta Byrska-Bishop; Rashmi Kanagal-Shamanna; Brynn Levy; Maximilian Schieck; Thomas Illig; Silviu-Alin Bacanu; Janet S Chou; Adrienne G Randolph; Amyn M Rojiani; Michael C Zody; Catherine A Brownstein; Alan H Beggs; Vineet Bafna; Erich D Jarvis; Alexander Hoischen; Alka Chaubey; Ravindra Kolhe Journal: iScience Date: 2022-01-10
Authors: Hoda A Ahmed; Ghada Y El-Kamah; Eman Rabie; Mostafa I Mostafa; Maha R Abouzaid; Nehal F Hassib; Mennat I Mehrez; Mohamed A Abdel-Kader; Yasmine H Mohsen; Suher K Zada; Khalda S Amr; Inas S M Sayed Journal: Genes (Basel) Date: 2021-09-08 Impact factor: 4.096