Mawaddah Ar Rochmah1, Hiroyuki Awano2, Tomonari Awaya3, Nur Imma Fatimah Harahap1, Naoya Morisada4, Yoshihiro Bouike5, Toshio Saito6, Yuji Kubo7, Kayoko Saito7, Poh San Lai8, Ichiro Morioka2, Kazumoto Iijima2, Hisahide Nishio9, Masakazu Shinohara1. 1. Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan. 2. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 3. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 4. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan. 5. Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan. 6. Division of Child Neurology, Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan. 7. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan. 8. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 9. Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: nishio@med.kobe-u.ac.jp.
Abstract
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1. Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies. SUBJECTS AND METHODS: From 33 families, 65 parents of genetically confirmed SMA patients were tested to determine SMA carrier status. Molecular genetic analyses, including multiplex ligation-dependent probe amplification (MLPA) assay, were performed using blood samples from family members. RESULTS: Of the 65 parents, three parents from three families had two SMN1 copies. Accordingly, the frequency of carriers with two SMN1 copies was 4.6%. Two of these families were further studied. Patient 1 was homozygous for SMN1 deletion. Patient 1's mother had two SMN1 copies on one chromosome, with deletion of SMN1 on the other chromosome ([2+0] genotype). Patient 1 inherited SMN1-deleted chromosomes from both parents. Patient 2 was compound heterozygous for two SMN1 mutations: whole-gene deletion and intragenic missense mutation, c.826T>C (p.Tyr276His). Patient 2's father had two SMN1 copies with the same intragenic mutation in one copy ([1+1d] genotype, d intragenic mutation). Patient 2 inherited the chromosome with an SMN1 mutation from the father and SMN1-deleted chromosome from the mother. CONCLUSION: SMA carriers with two SMN1 copies may be rare, but its possibility should be taken into consideration in carrier testing and counseling for SMA families or population-based carrier screening.
BACKGROUND:Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1. Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies. SUBJECTS AND METHODS: From 33 families, 65 parents of genetically confirmed SMA patients were tested to determine SMA carrier status. Molecular genetic analyses, including multiplex ligation-dependent probe amplification (MLPA) assay, were performed using blood samples from family members. RESULTS: Of the 65 parents, three parents from three families had two SMN1 copies. Accordingly, the frequency of carriers with two SMN1 copies was 4.6%. Two of these families were further studied. Patient 1 was homozygous for SMN1 deletion. Patient 1's mother had two SMN1 copies on one chromosome, with deletion of SMN1 on the other chromosome ([2+0] genotype). Patient 1 inherited SMN1-deleted chromosomes from both parents. Patient 2 was compound heterozygous for two SMN1 mutations: whole-gene deletion and intragenic missense mutation, c.826T>C (p.Tyr276His). Patient 2's father had two SMN1 copies with the same intragenic mutation in one copy ([1+1d] genotype, d intragenic mutation). Patient 2 inherited the chromosome with an SMN1 mutation from the father and SMN1-deleted chromosome from the mother. CONCLUSION: SMA carriers with two SMN1 copies may be rare, but its possibility should be taken into consideration in carrier testing and counseling for SMA families or population-based carrier screening.