Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

• Published in: American journal of medical genetics. Part A Vol. 185; no. 10; pp. 3068 - 3073
• Main Authors: Manaspon, Chawan, Boonsimma, Ponghatai, Phokaew, Chureerat, Theerapanon, Thanakorn, Sriwattanapong, Kanokwan, Porntaveetus, Thantrira, Shotelersuk, Vorasuk
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2021; Wiley Subscription Services, Inc
• Subjects: Adolescent; Alleles; Amino Acid Transport Systems, Acidic - deficiency; Amino Acid Transport Systems, Acidic - genetics; Antiporters - deficiency; Antiporters - genetics; Child; Child, Preschool; Developmental Disabilities - complications; Developmental Disabilities - genetics; Developmental Disabilities - pathology; dysmorphism; Female; Genealogy; Genotype; Genotypes; global developmental delay; Haplotypes; Haplotypes - genetics; Hereditary Central Nervous System Demyelinating Diseases - complications; Hereditary Central Nervous System Demyelinating Diseases - genetics; Hereditary Central Nervous System Demyelinating Diseases - pathology; Homozygote; Humans; hypomyelination; hypotonia; Leukodystrophy; Male; Microcephaly; Microcephaly - complications; Microcephaly - genetics; Microcephaly - pathology; Microencephaly; Mitochondrial Diseases - complications; Mitochondrial Diseases - genetics; Mitochondrial Diseases - pathology; Movement Disorders - complications; Movement Disorders - genetics; Movement Disorders - pathology; Mutation; Myelination; Patients; Pedigree; Phenotype; Phenotypes; Psychomotor Disorders - complications; Psychomotor Disorders - genetics; Psychomotor Disorders - pathology; Pyrroline Carboxylate Reductases - genetics; Spasticity; Young Adult; microcephaly; dysmorphism; hypomyelination; global developmental delay; hypotonia
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62365

PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three out of four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay. Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients.