Piranit Nik Kantaputra1,2, Prapai Dejkhamron3, Worrachet Intachai1, Chumpol Ngamphiw4, Katsushige Kawasaki5, Atsushi Ohazama5, Suttichai Krisanaprakornkit6,7, Bjorn Olsen8, Sissades Tongsima4, Jame R Ketudat Cairns9. 1. Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand. 2. Dentaland Clinic, Chiang Mai, Thailand. 3. Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 4. National Biobank of Thailand, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand. 5. Division of Oral Anatomy, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 6. Center of Excellence in Oral Biology, Chiang Mai University, Chiang Mai, Thailand. 7. Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand. 8. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA. 9. School of Chemistry, Institute of Science, and Center for Biomolecular Structure, Function and Application, Suranaree University of Technology, Nakhon Ratchasima, Thailand.
Abstract
BACKGROUND: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. OBJECTIVE: To report for the first time the molecular aetiology of JHS. PATIENT AND METHODS: Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. RESULTS: Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. CONCLUSIONS: Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.
BACKGROUND: Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. OBJECTIVE: To report for the first time the molecular aetiology of JHS. PATIENT AND METHODS: Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. RESULTS: Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. CONCLUSIONS: Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.
Authors: Venkataragavan Chandrasekaran; Nina Oparina; Maria-Jose Garcia-Bonete; Caroline Wasén; Malin C Erlandsson; Eric Malmhäll-Bah; Karin M E Andersson; Maja Jensen; Sofia T Silfverswärd; Gergely Katona; Maria I Bokarewa Journal: Front Immunol Date: 2022-02-10 Impact factor: 7.561