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Intellectual disability (ID) is a central nervous system disease that affects 2-3 % of the worldwide population. With a wide range of sign and symptoms, three major criteria make the diagnostic picture of intellectual disability: Intelligence quotient (IQ) less than 70, present symptoms before the age 18 and deficits in at least two adaptive behaviors [Prada 2016; Celis 2015].
This clinically heterogeneous disorder can develop due to genetic and /or environmental causes. Genetic risk factor, de novo or inherited, is considered responsible for 25-50 % of these cases and this rate increases with the ID severity [Prada 2016; Kaufman 2010; Celis 2015]. In this view, ID may be categorized in syndromic and non-syndromic forms.
Although more than 450 single candidate genes have been identified for Mendelian ID, but in half of cases the cause of disease remains unknown [Kaufman 2010]. The development of DNA sequencing technology over the past decade made dramatic era for discovery genetic etiology of ID. More than thirty studies were established to provide casual variants in various families, including sporadic or familial cases [Rabbani2014]. For instance, Najmabadi et al. reported 50 novel candidate genes in 136 Iranian families [Najmabadi 2011].
While approximately 1% of the genome (30 Mb) (~3 X10 7 base pairs) are the coding sequences [Rabbani 2014], it seems Whole Exome Sequencing (WES) strategy may be well- tool for the understanding of the genetic pathology of such clinically heterogeneous disorder. Using [WES/Trio WES], we detect a novel variant of GPT2 gene that influence all affected siblings of an Iranian family in homozygous pattern mutation.
The proband was a 23 yr. boy of a semi –large Iranian family, who had three affected sisters and three healthy sisters. He suffered from intellectual disability without any malformation.
After obtaining the signed informed consent from parents, a full clinical evaluation provided by the referring physician along with recording the family pedigree by our team’s geneticists. This study has Ethical approval of the AJA University of Medical Sciences in Tehran, Iran (code:???)
Briefly, after blood sample preparation, DNA extraction, genomic DNA fragment enrichment by >340,000 probes designed against the human genome (Nextera Rapid Capture Exome, Illumina) ; Library preparation on an Illumina NextSeq or HiSeq 4000 platforms (Illumina) was performed to an average coverage depth 70-100X.
Based on mode of family inheritance, multistep ﬁltering strategy was applied to narrow down the identiﬁed variants to a small number. Applying public databases such as 1000 Genome Project, dbSNP, ClinVar, SIFT, Polyphen, Mutation taster software and in-house databases (Iranome) to reach the possible causing variants.
Candidate variant was confirmed by using bidirectional direct sequencing for all of the family members (The primers and PCR reactions details are available upon request).
We report a semi- large family from a rural community in the Lourestan province of Iran. This family has four affected children and three healthy daughters without any history of still birth or abortion. The proband is a 23- year-old boy and his parents are first cosine. This family had no history of ID in their known ancestors.
According to the mother , the proband and all siblings had born with a normal occipitofrontal head circumference (OFC), birth weight and no prenatal complications at term birth. Their birth measurements are not available. His oldest sister and two affected siblings (II and III) were born by cesarean section and others by normal vaginal delivery (NVD).
The proband and his affected sisters display mild to-moderate developmental delay whether this delay continues with moderate motor impairments without progressive manner. There were no facial features such as ear malformations, but there is complain of hearing loss among them. Also, no obvious structural malformation other than microcephaly was seen. They showed difficulty in walking, but they could walk without support, although frequent falls were reported. Severe speech problems and language disabilities seem to be common features of them, but their talking are understandable. Aggressive and sensitive behavior is another common behavior in these patients. Despite self-help skills training, they required assistance with bathing and dressing.
Using exome sequencing, an average of 37 Mb of sequence was generated for proband (median read depth = ?, base pairs with >10 reads = ?%). Brieﬂy, after discarding reads, there were 70-100-fold coverage of the ~37 Mb mappable sequence that provide sufficient targeted bases (~97%) for passing our variant calling thresholds. Subsequently, the usual filters applied to exclude known variants (from dbSNP, SIFT, Polyphen , Mutation taster software and Iranome ).
We found a mutation in exon 3 of GPT2 (OMIM #616281) that changed an adenine for a guanine (c. 266 A>G), which resulted in an amino acid change in position 89 of the protein (p. Glu89Gly).
Using bidirectional direct sequencing, the same mutation (c.266A>G) was detected in all of family patients. Also heterozygous variant in the GPT2 gene was found in parents and one of unaffected siblings.
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