Clinical and genetic characterization of patients segregating variants in KPTN, MINPP1, NGLY1, AP4B1, and SON underlying neurodevelopmental disorders: Genetic and phenotypic expansion.

Autor: Ullah A; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Shah AA; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.; Center for Medical Genetics & Hunan Key laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China., Alluqmani M; Department of Biochemistry and Molecular Medicine, College of Medicine, Taibah University Medina, Medina, Saudi Arabia., Haider N; Shaheed Zulfiqar Ali Bhutto Medical University, Department of Pediatrics, Pakistan Institute of Medical Sciences, Islamabad, Pakistan., Aman H; Al-Amal Hospital, Ministry of Health, Medina, Saudi Arabia., Alfadhli F; Department of Genetics, Medina Maternity and Children Hospital, Medina, Saudi Arabia., Almatrafi AM; Department of Biology, College of Science, Taibah University Medina, Medina, Saudi Arabia., Albalawi AM; Center for Genetics and Inherited Diseases, Taibah University Medina, Medina, Saudi Arabia., Krishin J; Shaheed Zulfiqar Ali Bhutto Medical University, Department of Pediatrics, Pakistan Institute of Medical Sciences, Islamabad, Pakistan., Ullah Khan F; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Anjam BA; Shaheed Zulfiqar Ali Bhutto Medical University, Department of Pediatrics, Pakistan Institute of Medical Sciences, Islamabad, Pakistan., Abdullah; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Lozano EP; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Samad A; Department of Biochemistry, Abdul Wali khan Univeristy Mardan, Mardan, Pakistan., Ahmad W; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Xia K; Center for Medical Genetics & Hunan Key laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China., Basit S; Department of Biochemistry and Molecular Medicine, College of Medicine, Taibah University Medina, Medina, Saudi Arabia.; Center for Genetics and Inherited Diseases, Taibah University Medina, Medina, Saudi Arabia.
Jazyk: angličtina
Zdroj: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience [Int J Dev Neurosci] 2022 Dec; Vol. 82 (8), pp. 789-805. Date of Electronic Publication: 2022 Oct 11.
DOI: 10.1002/jdn.10231
Abstrakt: Neurodevelopmental disorders (NDDs) are heterogeneous genetic conditions of the central nervous system (CNS). Primary phenotypes of NDDs include epilepsy, loss of developmental skills, abnormal movements, muscle weakness, ocular anomalies, hearing problems, and macro- or microcephaly. NDDs occur due to variants in genes encoding proteins involved in the structure and function of CNS, thus interrupting its normal physiological role. In the study presented here, four consanguineous families (A-D), with members showing neurodevelopmental symptoms, were recruited for clinical and genetic characterization of the phenotypes. Clinical examinations, including Seguin Form Board Test (SFBT), Vineland Social Maturity Scale (VSMS), brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG), Electromyography (EMG), Nerve Conduction Velocity (NCV), and Magnetic Resonance Spectroscopy, were employed to characterize the disease phenotypes. Whole exome sequencing (WES) followed by Sanger sequencing was employed to search for the genetic basis of the neurological symptoms observed in four families (A-D). Two of these families (A, B) were of Saudi Arabian origin, and two others (C, D) were of Pakistan origin. Two homozygous missense (KPTN: NM_007059.4:c.301T>G: NP_008990.2; p.(Phe101Val) and MINPP1:NM_001178118.2:c.1202G>A: NP_001171588.1; p.(Arg401Gln)) variants in families A and B, respectively, and two homozygous nonsense (NGLY1:NM_018297.3:c.1534_1541dup: NP_060767.2; p.(Ser515LysfsTer51) and AP4B1:NM_001253852:c.1668G>A: NP_001240781.1; p.(Trp556X)) variants in families C and D, respectively, were identified. Interestingly, additional heterozygous nonsense variant in SON: NM_138927.2: c.5753_5756del: NP_620305.3; p.(Val1918GlufsTer87) and a homozygous variant in FLG (FLG: NM_002016.2:c.7339C>T: NP_002007.1; p.(Arg2447X) were detected in families A and D, respectively. Further, we determined the deleteriousness of each variant through computational approaches. The present study expands the phenotypic and genetic spectrum of NDD-associated genes (KPTN, MINPP1, NGLY1, and AP4B1). Moreover, additional nonsense variants (SON: c.5753_5756del and FLG: c.7339C>T) identified in two families segregating with the phenotype might explain the phenotypic variability and severity in our patients.
(© 2022 International Society for Developmental Neuroscience.)
Databáze: MEDLINE
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