Xiangyu Liu1, Jing Meng2,3, Jinhui Ma2,3,4, Jianbo Shu2,5, Chunyu Gu2,6, Xiaofang Chen2,6, Dong Li7,8, Chunquan Cai9,10,11. 1. School of Basic Medical Science, Tianjin Medical University, 300070, Tianjin, China. 2. Tianjin Children's Hospital (Children's Hospital of Tianjin University), No. 238 Longyan Road, Beichen District, 300134, Tianjin, China. 3. The Medical Department of Neurology, Tianjin Children's Hospital, No. 238 Longyan Road, Beichen District, 300134, Tianjin, China. 4. The Medical Department of Neurology Electroencephalogram room, Tianjin Children's Hospital, 300134, Tianjin, China. 5. Tianjin Pediatric Research Institute, 300134, Tianjin, China. 6. Graduate College of Tianjin Medical University, 300070, Tianjin, China. 7. Tianjin Children's Hospital (Children's Hospital of Tianjin University), No. 238 Longyan Road, Beichen District, 300134, Tianjin, China. lidongtjetyy@163.com. 8. The Medical Department of Neurology, Tianjin Children's Hospital, No. 238 Longyan Road, Beichen District, 300134, Tianjin, China. lidongtjetyy@163.com. 9. Tianjin Children's Hospital (Children's Hospital of Tianjin University), No. 238 Longyan Road, Beichen District, 300134, Tianjin, China. cqcns6@126.com. 10. Tianjin Pediatric Research Institute, 300134, Tianjin, China. cqcns6@126.com. 11. Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, 300134, Tianjin, China. cqcns6@126.com.
Abstract
BACKGROUND: PIGA (PIG class A) gene codes for the PIG-A protein, which is a catalytic subunit of GPI-GlcNAc transferase. GPI-anchored proteins play an important role in the metabolism of mammals. Somatic variants of PIGA genes in bone marrow hematopoietic stem cells often result in paroxysmal nocturnal haemoglobinuria, and the germline PIGA variants cause multiple congenital anomalies hypotonia seizures syndrome 2 (MCAHS2) because of glycosylphosphatidylinositol metabolic abnormalities. METHODS: Whole exome sequencing was performed on peripheral blood sample of the patient with MCAHS2. A novel germline PIGA variant was found, and Sanger sequencing was performed as verification for the variant. After that, we used the keywords to retrieve relevant reports and provided a literature review. RESULTS: A novel hemizygous germline PIGA variant (NM_002641.3:c.971G > A) at exon4 was identified through whole exome sequencing. And it was a highly probable pathogenic variant. Sanger sequencing yielded consistent results. The missense variant cause change of p.(Cys324Tyr) in the transcription product according to the predicted outcomes. CONCLUSION: We reported a case of MCAHS2 caused by a novel PIGA variant. Following a review of the literature, we suggested that MCAHS2 should be considered as a disorder spectrum consisting of core symptoms, multi-system impairment, and premature death. The core symptoms include hypotonia, psychomotor delay, epilepsy (intractable epilepsy mostly) and early death. Core symptoms nearly happened to almost all patients. Meanwhile, MCAHS2 involves a wide range of organ and system impairments with changeable form.
BACKGROUND: PIGA (PIG class A) gene codes for the PIG-A protein, which is a catalytic subunit of GPI-GlcNAc transferase. GPI-anchored proteins play an important role in the metabolism of mammals. Somatic variants of PIGA genes in bone marrow hematopoietic stem cells often result in paroxysmal nocturnal haemoglobinuria, and the germline PIGA variants cause multiple congenital anomalies hypotonia seizures syndrome 2 (MCAHS2) because of glycosylphosphatidylinositol metabolic abnormalities. METHODS: Whole exome sequencing was performed on peripheral blood sample of the patient with MCAHS2. A novel germline PIGA variant was found, and Sanger sequencing was performed as verification for the variant. After that, we used the keywords to retrieve relevant reports and provided a literature review. RESULTS: A novel hemizygous germline PIGA variant (NM_002641.3:c.971G > A) at exon4 was identified through whole exome sequencing. And it was a highly probable pathogenic variant. Sanger sequencing yielded consistent results. The missense variant cause change of p.(Cys324Tyr) in the transcription product according to the predicted outcomes. CONCLUSION: We reported a case of MCAHS2 caused by a novel PIGA variant. Following a review of the literature, we suggested that MCAHS2 should be considered as a disorder spectrum consisting of core symptoms, multi-system impairment, and premature death. The core symptoms include hypotonia, psychomotor delay, epilepsy (intractable epilepsy mostly) and early death. Core symptoms nearly happened to almost all patients. Meanwhile, MCAHS2 involves a wide range of organ and system impairments with changeable form.
Authors: Alexej Knaus; Jean Tori Pantel; Manuela Pendziwiat; Nurulhuda Hajjir; Max Zhao; Tzung-Chien Hsieh; Max Schubach; Yaron Gurovich; Nicole Fleischer; Marten Jäger; Sebastian Köhler; Hiltrud Muhle; Christian Korff; Rikke S Møller; Allan Bayat; Patrick Calvas; Nicolas Chassaing; Hannah Warren; Steven Skinner; Raymond Louie; Christina Evers; Marc Bohn; Hans-Jürgen Christen; Myrthe van den Born; Ewa Obersztyn; Agnieszka Charzewska; Milda Endziniene; Fanny Kortüm; Natasha Brown; Peter N Robinson; Helenius J Schelhaas; Yvonne Weber; Ingo Helbig; Stefan Mundlos; Denise Horn; Peter M Krawitz Journal: Genome Med Date: 2018-01-09 Impact factor: 11.117
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