Identification and In Silico Characterization of a Novel Point Mutation within the Phosphatidylinositol Glycan Anchor Biosynthesis Class G Gene in an Iranian Family with Intellectual Disability
Intellectual disability (ID) is characterized by limited mental ability and adaptive behavior that imposes a heavy burden on the patients’ families and the health care system. This study was aimed at determining the molecular aspect of nonsyndromic ID, in a family from South Khorasan Province in Iran. Exome sequencing was performed, as well as complete clinical examinations of the family. Afterward, in silico studies have been done to examine the changes that occurred in the protein structure, in association with the ID phenotype. The PIGG (NC_000004.12) mutation was found on Chr 4:517639G>A, and this chromosomal location was proposed as the disorder-causing variant. This Arg658Gln alteration was confirmed by Sanger sequencing, using specific primers for PIGG. In conclusion, our study indicated a novel mutation in the PIGG in the affected family. This mutation is a novel variant (p. R658Q) with an autosomal recessive inheritance pattern. These findings could improve genetic counseling in the future.
KeywordsIntellectual disability Whole-exome sequencing In silico South Khorasan
The authors thank all the subjects who willingly participated in this research.
This work was financially supported by a research grant from Birjand University of Medical Science.
Compliance with Ethical Standards
A clinical geneticist obtained all exams and informed consent from every member of the family. In this study, the entire procedures were conducted according to the Helsinki Declaration and ethical standards of the institutional research committee. The ethics code was taken from Birjand University of Medical Sciences (Ir.bums. REC.1396.350).
Conflict of Interest
The authors declare that they have no conflict of interest.
- Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, Mollica L, Crawford DH, Baker A, Ferguson M, Roberts I, Houlston R, Kinoshita T, Karadimitris A (2006) Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 12:846–851CrossRefGoogle Scholar
- Hamdan FF et al (2009) Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation N Engl J med 360:599-605Google Scholar
- Hamdan et al (2014) De novo mutations in moderate or severe intellectual disability. PLOS e1004772 https://www.ncbi.nlm.nih.gov/gene/54872
- Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–299CrossRefGoogle Scholar
- Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MAW, Kleefstra T, Kramer JM, Webber C, Huynen MA, Schenck A (2016) Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 98:149–164CrossRefGoogle Scholar
- Kortum F, Das S, Flindt M, Morris-Rosendahl DJ, Stefanova I, Goldstein A, Horn D, Klopocki E, Kluger G, Martin P, Rauch A, Roumer A, Saitta S, Walsh LE, Wieczorek D, Uyanik G, Kutsche K, Dobyns WB (2011) The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet 48:396–406CrossRefGoogle Scholar
- Krawitz PM, Murakami Y, Hecht J, Krüger U, Holder SE, Mortier GR, Delle Chiaie B, de Baere E, Thompson MD, Roscioli T, Kielbasa S, Kinoshita T, Mundlos S, Robinson PN, Horn D (2012) Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. Am J Hum Genet 91:146–151CrossRefGoogle Scholar
- Makrythanasis P, Kato M, Zaki MS, Saitsu H, Nakamura K, Santoni FA, Miyatake S, Nakashima M, Issa MY, Guipponi M, Letourneau A, Logan CV, Roberts N, Parry DA, Johnson CA, Matsumoto N, Hamamy H, Sheridan E, Kinoshita T, Antonarakis SE, Murakami Y (2016) Pathogenic variants in PIGG cause intellectual disability with seizures and hypotonia. Am J Hum Genet 98:615–626CrossRefGoogle Scholar
- Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, Albin-Kaplanski A, Maya I, Magal N, Birk E, Simon AJ, Halevy A, Rechavi G, Shohat M, Straussberg R, Basel-Vanagaite L (2011) Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet 48:383–389CrossRefGoogle Scholar
- Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764CrossRefGoogle Scholar
- National Academies of Sciences E, and Medicine, Instituteof Medicine, Board on Children, Youth, and Families, Board on theHealth of Select Populations, Committee to Evaluate the Supplemental Security Income Disability Program for Children with Mental Disorders (2015) Prevalence of intellectual disabilities. In: Wu JT, Boat TF (eds) Mental disorders and disabilities among low-income children. National Academies Press, WashingtonGoogle Scholar
- Novo-Filho GM, Montenegro MM, Zanardo ÉA, Dutra RL, Dias AT, Piazzon FB, Costa TVMM, Nascimento AM, Honjo RS, Kim CA, Kulikowski LD (2016) Subtelomeric copy number variations: the importance of 4p/4q deletions in patients with congenital anomalies and developmental disability. Cytogenet Genome Res 149:241–246CrossRefGoogle Scholar
- Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schröck E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–1682CrossRefGoogle Scholar