The Identification and Stereochemistry Analysis of a Novel Mutation p.(D367Tfs*61) in the CYP1B1 Gene: A Case Report.

PURPOSE: To investigate the presence of a probable genetic defect(s) that may cause primary congenital glaucoma (PCG) in a seven-year-old female patient. METHODS: A seven-year-old female patient and her family received genetic counseling and underwent full clinical examinations by an expert ophthalmologist. The patient's genomic DNA was subjected to the targeted gene capture and next-generation sequencing (NGS) along with Sanger sequencing method. The 3D structure prediction and stereochemistry analysis were performed for both mutant and wild-type forms of the CYP1B1 protein. RESULTS: The clinical examinations indicated that the diagnosis of PCG was correctly made. We identified a novel homozygous deletion in which a "C" nucleotide was deleted from the final exon of the Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) gene. The 3D molecular modeling of the CYP1B1 protein predicted significant structural changes could occur in this protein as a result of the mutation mentioned earlier. The stereochemistry analysis revealed mutant features of the protein, as well as significant misfolding and possible malfunctions in the mutant form of the CYP1B1 protein. CONCLUSIONS: This mutation might cause a frameshift in the translation process, leading to the malfunction of the CYP1B1 protein and development of glaucoma. This newly-identified mutation could be regarded as potential deletion mutation in genetic counseling and molecular examination for the detection of PCG disease in Iran.

Possible dual contribution of a novel GUCY2D mutation in the development of retinal degeneration in a consanguineous population.

Molecular characterization of novel mutations in Leber Congenital Amaurosis (LCA) disease improves the disease diagnosis and contributes to the development of preventive and therapeutic approaches. We studied an isolated inbred population in Iran with a high prevalence of retinal degeneration with clinical variability. The clinical examinations were performed on eight patients belonging to three consanguineous families. The identical-by-descent (IBD) mapping technique was employed to identify the shared loci in patients. Subsequently, Sanger sequencing of the GUCY2D gene, in silico analysis, as well as segregation study were conducted. The whole-exome sequencing method was applied for negative cases of GUCY2D mutation, followed by segregation study in suspected variants among families. A novel deletion mutation in the GUCY2D gene can explain the emergence of LCA-1 in most patients but not all. Besides, a heterozygous variant of uncertain significance (VUS) was observed in the BEST1 gene in some healthy and participant patients. These results further support inter/intra-familial clinical heterogeneity in retinal dystrophy and suggest that screening the GUCY2D gene would be needed for the diagnosis of LCA in Iranian people living in the central regions. The variant in the BEST1 gene might be considered a benign heterozygous variant; however, we hypothesized a possible double heterozygosity in both GUCY2D and BEST1 genes that may cause the pathogenesis of cone-rod dystrophy-6 (CRD-6) disease. This would propose a new scenario for the pathogenesis of a monogenic disorder such as CRD-6 disease in which other genetic elements may be involved in the development of the disease.

A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report.

PURPOSE: To investigate genetic mutation(s) underlying retinal degeneration in a male patient. METHODS: A seven-year-old male patient was referred to receive genetic counseling and molecular testing. Clinical examination was performed by slit-lamp examination and electroretinography (ERG). Molecular testing was undertaken through arrayed-primer extension (APEX) and Sanger sequencing. RESULTS: Slit-lamp examination and flat ERG were in favor of Leber congenital amaurosis (LCA) disease as well as fundus findings. The genetic screening revealed two novel homozygote deletion and duplication variants in intron 15 and exon 16 of the GUCY2D gene. Segregation analysis in the family supports the probable contribution of these two novel mutations in clinical representations of the patient. CONCLUSIONS: This report provides more information about LCA disease and its relevant mutations in Iran. Considering the overlapping phenotypes observed in retinal degenerative disorders, comprehensive molecular testing is needed for precise diagnosis.

A novel 8-bp duplication in ADAT3 causes mild intellectual disability.

Inosine is a base located at wobble position 34 of the tRNA anticodon stem-loop, enabling the recognition of more than one codon in the translation process. A heterodimer consists of ADAT3 and ADAT2 and is involved in the adenosine-to-inosine conversion in tRNA. Here, we report the second novel ADAT3 mutation in a patient with microcephaly, intellectual disability, and hyperactivity. These findings constitute a second mutation and expand the clinical spectrum of extremely rare ADAT3 mutations.

Another Novel Missense Mutation in ARSB Gene in Iran.

Mucopolysaccharidosis VI (MPS-VI) is an infrequent autosomal recessive disorder caused by mutations in ARSB gene and deficiency in lysosomal enzyyme ARSB activities subsequently. This enzyme is essential for the breaking of glycosaminoglycans (GAGs) such as dermatan sulfate and chondroitin sulfate. ARSB dysfunction results in imperfect breakdown of GAGs and their accumulation in urine. Mutations in ARSB gene are the main players in MPS-VI disease and its clinical consequences. Most reported mutations are point mutations but there are some other examples in literature. Here we report a novel missense mutation in ARSB gene that is inherited as an autosomal recessive mode and probably explain the clinical status of the proband. This mutation replaces the threonine 92 by proline and alters ARSB structure. This is the most feasible scenario for clinical condition we described here. This novel mutation should be remarked for PND and PGD to improve the health and management of such families.

Kleefstra Syndrome: The First Case Report From Iran.

Kleefstra Syndrome is characterized by severe mental retardation, brachycephaly, microcephaly, epileptic seizures, distinct facial features, and infantile weak muscle tone and heart defects. Deletion of EHMT1 is the main player in 75% of cases. Because of blurriness in genotype-phenotype correlation through clinical and molecular features of both 9q34.3 microdeletion patients and those with an intragenic EHMT1 mutation in Kleefstra Syndrome, genetic characterization of patients with clinical symptoms of such spectrum is desirable. We report the first Kleefstra Syndrome patient in Iran characterized through genetic approaches. Our report could improve KS diagnosis in Iran and prepare PND and PGs options for involved families.