Biallelic missense variants in ZBTB11 can cause intellectual disability in humans.

Exploring genes and pathways underlying intellectual disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next-generation sequencing revealed Zinc Finger and BTB Domain Containing 11 (ZBTB11) as a novel candidate ID gene. ZBTB11 encodes a little-studied transcription regulator, and the two identified missense variants in this study are predicted to disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding. Using HEK293T cells transfected with wild-type and mutant GFP-ZBTB11 constructs, we found the ZBTB11 mutants being excluded from the nucleolus, where the wild-type recombinant protein is predominantly localized. Pathway analysis applied to ChIP-seq data deposited in the ENCODE database supports the localization of ZBTB11 in nucleoli, highlighting associated pathways such as ribosomal RNA synthesis, ribosomal assembly, RNA modification and stress sensing, and provides a direct link between subcellular ZBTB11 location and its function. Furthermore, given the report of prominent brain and spinal cord degeneration in a zebrafish Zbtb11 mutant, we investigated ZBTB11-ortholog knockdown in Drosophila melanogaster brain by targeting RNAi using the UAS/Gal4 system. The observed approximate reduction to a third of the mushroom body size-possibly through neuronal reduction or degeneration-may affect neuronal circuits in the brain that are required for adaptive behavior, specifying the role of this gene in the nervous system. In conclusion, we report two ID families segregating ZBTB11 biallelic mutations disrupting Zn2+-binding motifs and provide functional evidence linking ZBTB11 dysfunction to this phenotype.

Heterozygosity for the Novel HBA2: c.*91_*92delTA Polyadenylation Site Variant on the α2-Globin Gene Expanding the Genetic Spectrum of α-Thalassemia in Iran.

There are four copy numbers of α-globin genes (16p13.3) in the human genome and the number of defective α-globin genes dictates the severity of α-thalassemia (α-thal). Mutations that occur in the 3' untranslated region (3'UTR), and especially at the polyadenylation (polyA) sites, affect the translation, stability and export of mRNA. A patient with hypochromic microcytic anemia was referred to the Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran by the health network. Molecular analysis of genomic DNA for the evaluation of mutations on the α- and ß-globin genes was performed. Direct sequencing of the hemoglobin (Hb) subunit α2 (HBA2) gene revealed a two nucleotide deletion between +816 and +817 in the 3'UTR, located at the polyA site, which seems to be a novel pathogenic variant. This novel variant expands the genetic spectrum of α-thal in the 3'UTR of the HBA2 gene.

Effect of inbreeding on intellectual disability revisited by trio sequencing.

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.

Frequency of α-Globin Gene Triplications and Coinheritance with ß-Globin Gene Mutations in the Iranian Population.

Numerical variation in α-globin genes is very important due to their roles as an effective factor for phenotype presentation. An unequal crossover from misalignment of a homologous sequence of an α-globin gene during meiosis can produce a numerical alteration. A single α-globin gene deletion is the most frequent mutation in α-thalassemia (α-thal) worldwide, while the additional α-globin chain is relatively common. The excess α-globin gene plays a critical role in pathophysiology of thalassemia, especially when in coinherited with ß-thalassemia (ß-thal). α-Globin triplication leads to an imbalanced ratio between α- and ß-globin chains, thus, it can exacerbate the clinical and hematological features of ß-thal. Different studies have been performed in various countries to determine the frequency of α-globin triplication and its genotype-phenotype correlation with ß-thal. In this study, we focused on the frequency of α-globin gene triplication and its characterization, either solely or in coexistence with ß-globin gene mutations in Iranian populations. We have investigated the α-globin gene rearrangements in 4010 individuals from different provinces of Iran with normal to abnormal hematological parameters. In total, the frequency of the αααanti 3.7 triplication was 1.7% and phenotype aggravation was observed in α-globin triplication patients who were carriers of ß-thal. Therefore, identification of genotype-phenotype correlation of α-globin triplication with ß-thal can be very useful for predicting the severity of clinical manifestations during genetic counseling.

Identification of causative gene mutation in an Iranian family with coloboma and nephropathy using whole exome sequencing.

Pathogenic variants in FAT1 gene have recently been described in association with coloboma, nephropathy, and facial dismorphism. Here we describe a 5-year-old Iranian boy with iris coloboma and nephropathy, born to an Iranian family. Extracted genomic DNA from blood sample was used to perform whole exome sequencing in the patient. The mutational screening revealed a homozygote Fat1 gene mutation c.5320A > G (p.17747Val), not previously reported in homozygote state in Iran. Our findings establish FAT1 as a gene with pleiotropic effects in human, emphasizing it as one of the causative genes in syndromic nephropathies.