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A novel missense variant in GPT2 causes non-syndromic autosomal recessive intellectual disability in a consanguineous Iranian family. 2020

Sima Binaafar, and Ehsan Razmara, and Nejat Mahdieh, and Hamidreza Sahebjame, and Ali Reza Tavasoli, and Masoud Garshasbi
Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.

Intellectual disability (ID) affects 1-3% of the general population worldwide. Genetic factors play an undeniable role in the etiology of Non-Syndromic Intellectual disability (NS-ID). Nowadays, whole-exome sequencing (WES) technique is used frequently to identify the causative genes in such heterogeneous diseases. Herein, we subjected four patients with initial diagnostics of NS-ID in a consanguineous Iranian family. To find the possible genetic cause(s), Trio-WES was performed on the proband and his both healthy parents. Sanger sequencing was performed to confirm the identified variant by WES and also investigate whether it co-segregates with the patients' phenotype in the family. Using several online in-silico predictors, the probable impacts of the variant on structure and function of GPT2 protein were predicted. A novel variant, c.266A>G; p.(Glu89Gly), in exon 3 of GPT2 (NM_133443.3) was identified using Trio-WES. The candidate variant was also verified by Sanger sequencing. All affected members showed the common clinical features suffering from a non-progressive mild-to-severe ID. Also, different clinical observations compared to previously reported cases such as no facial features, no obvious structural malformations, ability to speak but with difficulty, and lack of any morphological defects were noted for the first time in this family. The c.266A>G; p.(Glu89Gly) variant reported here is the sixth variant identified up to now in the GPT2 gene, to be associated with NS-ID. Our data support the potential malfunction of the substituted GPT2 protein resulted from the novel variant, however, we strongly suggest confirming this finding more by doing functional analysis.

UI MeSH Term Description Entries
D008297 Male Males
D008607 Intellectual Disability Subnormal intellectual functioning which originates during the developmental period. This has multiple potential etiologies, including genetic defects and perinatal insults. Intelligence quotient (IQ) scores are commonly used to determine whether an individual has an intellectual disability. IQ scores between 70 and 79 are in the borderline range. Scores below 67 are in the disabled range. (from Joynt, Clinical Neurology, 1992, Ch55, p28) Disability, Intellectual,Idiocy,Mental Retardation,Retardation, Mental,Deficiency, Mental,Intellectual Development Disorder,Mental Deficiency,Mental Retardation, Psychosocial,Deficiencies, Mental,Development Disorder, Intellectual,Development Disorders, Intellectual,Disabilities, Intellectual,Disorder, Intellectual Development,Disorders, Intellectual Development,Intellectual Development Disorders,Intellectual Disabilities,Mental Deficiencies,Mental Retardations, Psychosocial,Psychosocial Mental Retardation,Psychosocial Mental Retardations,Retardation, Psychosocial Mental,Retardations, Psychosocial Mental
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D010375 Pedigree The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition. Family Tree,Genealogical Tree,Genealogic Tree,Genetic Identity,Identity, Genetic,Family Trees,Genealogic Trees,Genealogical Trees,Genetic Identities,Identities, Genetic,Tree, Family,Tree, Genealogic,Tree, Genealogical,Trees, Family,Trees, Genealogic,Trees, Genealogical
D002648 Child A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL. Children
D003241 Consanguinity The magnitude of INBREEDING in humans. Inbreeding, Human,Consanguineous Marriage,Consanguinous Mating,Consanguineous Marriages,Consanguinities,Consanguinous Matings,Human Inbreeding,Human Inbreedings,Inbreedings, Human,Marriage, Consanguineous,Marriages, Consanguineous,Mating, Consanguinous,Matings, Consanguinous
D005260 Female Females
D005808 Genes, Recessive Genes that influence the PHENOTYPE only in the homozygous state. Conditions, Recessive Genetic,Genetic Conditions, Recessive,Recessive Genetic Conditions,Condition, Recessive Genetic,Gene, Recessive,Genetic Condition, Recessive,Recessive Gene,Recessive Genes,Recessive Genetic Condition
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072417 Protein Domains Discrete protein structural units that may fold independently of the rest of the protein and have their own functions. Peptide Domain,Protein Domain,Domain, Peptide,Domain, Protein,Domains, Peptide,Domains, Protein,Peptide Domains

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