Fatemeh Bitarafan1, Mehrnoosh Khodaeian2, Navid Almadani3, Alireza Kalhor4, Elham Amjadi Sardehaei2, Masoud Garshasbi5. 1. Department of Cellular and Molecular Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran. 2. Department of Medical Genetics, DeNA Laboratory, Tehran, Iran. 3. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran. 4. Department of medical science, Qom branch, Islamic Azad University, Qom, Iran. 5. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Teheran, Iran.
Abstract
BACKGROUND: Pathogenic variants within polynucleotide kinase 3'phosphatase (PNKP) gene cause microcephaly, seizures, and developmental delay (MCSZ) and ataxia-oculomotor apraxia type 4 (AOA4) disorders due to unrepaired DNA lesions. METHODS: Whole exome sequencing was performed on a child with microcephaly, seizures, developmental delay, callosal dysgenesis on MRI, intellectual disability, speech disorder, hyperactivity, and ataxic gait. RESULTS: Two heterozygous mutations in the PKNP gene, a novel intronic frameshift variant c.1298 + 33_1299-24del and a previously reported duplication, c.1253_1269dup; p.Thr424Glyfs*49 in exon 14 were identified. Both of these mutations affect the DNA kinase domain of PKNP. CONCLUSIONS: Our finding along with previous studies provide more evidence of the clinical heterogeneity of diseases caused by mutations in PNKP which makes its clinical diagnosis difficult and highlights the importance of genetic testing to unravel the cause of these diseases.
BACKGROUND: Pathogenic variants within polynucleotide kinase 3'phosphatase (PNKP) gene cause microcephaly, seizures, and developmental delay (MCSZ) and ataxia-oculomotor apraxia type 4 (AOA4) disorders due to unrepaired DNA lesions. METHODS: Whole exome sequencing was performed on a child with microcephaly, seizures, developmental delay, callosal dysgenesis on MRI, intellectual disability, speech disorder, hyperactivity, and ataxic gait. RESULTS: Two heterozygous mutations in the PKNP gene, a novel intronic frameshift variant c.1298 + 33_1299-24del and a previously reported duplication, c.1253_1269dup; p.Thr424Glyfs*49 in exon 14 were identified. Both of these mutations affect the DNA kinase domain of PKNP. CONCLUSIONS: Our finding along with previous studies provide more evidence of the clinical heterogeneity of diseases caused by mutations in PNKP which makes its clinical diagnosis difficult and highlights the importance of genetic testing to unravel the cause of these diseases.
Authors: Carlos Marcilla Vázquez; María Del Carmen Carrascosa Romero; Andrés Martínez Gutiérrez; María Baquero Cano; Blanca Alfaro Ponce; María Jesús Dabad Moreno Journal: J Pediatr Genet Date: 2020-05-12