Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Expanding the molecular and clinical phenotypes of FUT8-CDG.

Pathogenic variants in the Golgi localised alpha 1,6 fucosyltransferase, FUT8, cause a rare inherited metabolic disorder known as FUT8-CDG. To date, only three affected individuals have been reported presenting with a constellation of symptoms including intrauterine growth restriction, severe delays in growth and development, other neurological impairments, significantly shortened limbs, respiratory complications, and shortened lifespan. Here, we report an additional four unrelated affected individuals homozygous for novel pathogenic variants in FUT8. Analysis of serum N-glycans revealed a complete lack of core fucosylation, an important diagnostic biomarker of FUT8-CDG. Our data expands both the molecular and clinical phenotypes of FUT8-CDG and highlights the importance of identifying a reliable biomarker for confirming potentially pathogenic variants.

A novel pathogenic variant in the MARVELD2 gene causes autosomal recessive non-syndromic hearing loss in an Iranian family.

BACKGROUND AND AIMS: Hearing loss (HL) is the most common sensorineural disorder and one of the most common human defects. HL can be classified according to main criteria, including: the site (conductive, sensorineural and mixed), onset (pre-lingual and post-lingual), accompanying signs and symptoms (syndromic and non-syndromic), severity (mild, moderate, severe and profound) and mode of inheritance (Autosomal recessive, autosomal dominant, X-linked and mitochondrial). Autosomal recessive non-syndromic HL (ARNSHL) forms constitute a major share of the HL cases. In the present study, next-generation sequencing (NGS) was applied to investigate the underlying etiology of HL in a multiplex ARNSHL family from Khuzestan province, southwest Iran. METHODS: In this descriptive study, 20 multiplex ARNSHL families from Khuzestan province, southwest of Iran were recruited. After DNA extraction, genetic linkage analysis (GLA) was applied to screen for a panel of more prevalent loci. One family, which was not linked to these loci, was subjected to Otogenetics deafness Next Generation Sequencing (NGS) panel. RESULTS: NGS results showed a novel deletion-insertion variant (c.1555delinsAA) in the MARVELD2 gene. The variant which is a frameshift in the seventh exon of the MARVELD2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. CONCLUSION: NGS is very promising to identify the molecular etiology of highly heterogeneous diseases such as HL. MARVELD2 might be important in the etiology of HL in this region of Iran.

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing.

BACKGROUND AND OBJECTIVES: Hereditary hearing loss (HL) is known by a very high genetic heterogeneity, which makes a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. METHOD: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 3 affected members. After excluding mutations in the GJB2 and 7 other most common autosomal recessive nonsyndromic HL genes via Sanger sequencing and genetic linkage analysis in the family, we applied the Otogenetics deafness NGS panel in the proband of this family. RESULTS: NGS results showed a novel rare variant (c.7720C>T) in the MYO15A gene. This nonsense variant in the exon 40 of the MYO15A gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics guideline. CONCLUSIONS: New DNA sequencing technologies could lead to identification of the disease causing variants in highly heterogeneous disorders such as HL.

A pathogenic variant in SLC26A4 is associated with Pendred syndrome in a consanguineous Iranian family.

Objective: Hearing loss (HL) is a common sensory deficit with high phenotypic and genotypic heterogeneity. A large Iranian family with HL was genetically assessed in this study. Design: A proband from a consanguineous multiplex HL family from Iran was examined via Targeted Next-Generation Sequencing (TNGS). Sanger sequencing allowed the segregation analysis of the variant of interest and the investigation of its presence in a cohort of 50 ethnicity-matched healthy control individuals. The gene was previously associated with HL. Therefore, to determine whether the variant was specifically associated with Pendred Syndrome (PDS) or DFNB4, biochemical analyses, PTA, thyroid scans by Tc99m, perchlorate discharge test and high-resolution CT scan of the temporal bone were carried out on the affected family members. Study sample: Ten members of a large multiplex Iranian family with HL were recruited in this study. In addition, 50 unrelated healthy controls of the same ethnic group were randomly selected to genotype the variant. Results: A homozygous missense variant (NM_000441.1: c.1211C > T/p.Thr404Ile) in exon 10 was found segregating in the family. Based on the ACMG's guidelines, the variant was classified as pathogenic. Conclusion: This study expands the spectrum of SLC26A4 pathogenic variants in hearing loss.

Identification of Candidate Genes for Pigmentation in Camels Using Genotyping-by-Sequencing.

The coat color of dromedary is usually uniform and varies from black to white, although dark- to light-brown colors are the most common phenotypes. This project was designed to gain knowledge on novel color-related variants using genotyping-by-sequencing (GBS). The association between the SNPs and coat color was tested using MLM (mixed linear models) with kinship matrix. Three GWAS models including white color vs. non-white color, black vs. non-black color, and light-brown vs. dark-brown color were performed. There were no distinct genetic clusters detected based on the color phenotypes. However, admixture occurred among all individuals of the four different coat color groups. We identified nine significant SNPs associated with white color after Bonferroni correction, located close to ANKRD26, GNB1, TSPYL4, TEKT5, DEXI, CIITA, TVP23B, CLEC16A, TMPRSS13, FXYD6, MPZL3, ANKRD26, HFM1, CDC7, TGFBR3, and HACE1 genes in neighboring flanking regions. The 13 significant SNPs associated with black color and the candidate genes were: CAPN7, CHRM4, CIITA, CLEC16A, COL4A4, COL6A6, CREB3L1, DEXI, DGKZ, DGKZ, EAF1, HDLBP, INPP5F, MCMBP, MDK, SEC23IP, SNAI1, TBX15, TEKT5, TMEM189, trpS, TSPYL4, TVP23B, and UBE2V1. The SNAI1 gene interacted with MCIR, ASIP and KIT genes. These genes play a key role in the melanin biosynthetic and pigmentation biological process and melanogenesis biological pathway. Further research using a larger sample size and pedigree data will allow confirmation of associated SNPs and the identified candidate genes.

Investigating the association between common DRD2/ANKK1 genetic polymorphisms and schizophrenia: a meta-analysis.

Genetic factors play an important role in the pathogenesis of schizophrenia. Dysregulations in the dopaminergic system have long been known to play an influential role in the development of this disorder. Although a large number of studies have investigated the association between genetic polymorphisms in the genes involved in this system and the risk of schizophrenia, the results have been inconsistent. In this meta-analysis, we searched for publications in Ovid Medline, Embase, Web of Science (science citation index expanded), and PsycNET for articles published until January 2020. We identified case-control studies investigating the association between four common genetic polymorphisms (rs6277, rs1799732, rs1800497, and rs1801028) and the risk of schizophrenia. The studies were subsequently selected according to the predefined inclusion and exclusion criteria. The data extraction was conducted according to the PRISMA guidelines.We also assessed the quality of the studies and investigated publication bias using funnel plot and Egger's regression test. The association analysis was conducted in allelic, dominant, and recessive genetic models. Subsequently, bioinformatics analysis of the effect of the polymorphisms found to be significantly associated with schizophrenia on protein stability, posttranslational modifications, and 3D protein structure was conducted. This meta-analysis showed that Taq1A (allelic model: OR, 0.856, 95% CI, 0.734-0.998) has a protective effect against the development of schizophrenia. Further, it was found that this variant may decreaseANKK1protein stability. Further, this polymorphism was found to lead to the gain of modifications sites for ubiquitination (Ubi. score =-1.894) and methylation (Meth. score =-0.834). Several genetic factors contribute to the susceptibility of schizophrenia. The updated knowledge emerging from this meta-analysis showing the protective effect of rs1800497 polymorphism (Taq1A) can shed light on the role of Taq1A polymorphism in the susceptibility to schizophrenia and also pave way for further functional studies investigating the role of ANKK1 protein in the pathogenesis of schizophrenia.

Genomic prediction for growth using a low-density SNP panel in dromedary camels.

For thousands of years, camels have produced meat, milk, and fiber in harsh desert conditions. For a sustainable development to provide protein resources from desert areas, it is necessary to pay attention to genetic improvement in camel breeding. By using genotyping-by-sequencing (GBS) method we produced over 14,500 genome wide markers to conduct a genome- wide association study (GWAS) for investigating the birth weight, daily gain, and body weight of 96 dromedaries in the Iranian central desert. A total of 99 SNPs were associated with birth weight, daily gain, and body weight (p-value < 0.002). Genomic breeding values (GEBVs) were estimated with the BGLR package using (i) all 14,522 SNPs and (ii) the 99 SNPs by GWAS. Twenty-eight SNPs were associated with birth weight, daily gain, and body weight (p-value < 0.001). Annotation of the genomic region (s) within ± 100 kb of the associated SNPs facilitated prediction of 36 candidate genes. The accuracy of GEBVs was more than 0.65 based on all 14,522 SNPs, but the regression coefficients for birth weight, daily gain, and body weight were 0.39, 0.20, and 0.23, respectively. Because of low sample size, the GEBVs were predicted using the associated SNPs from GWAS. The accuracy of GEBVs based on the 99 associated SNPs was 0.62, 0.82, and 0.57 for birth weight, daily gain, and body weight. This report is the first GWAS using GBS on dromedary camels and identifies markers associated with growth traits that could help to plan breeding program to genetic improvement. Further researches using larger sample size and collaboration of the camel farmers and more profound understanding will permit verification of the associated SNPs identified in this project. The preliminary results of study show that genomic selection could be the appropriate way to genetic improvement of body weight in dromedary camels, which is challenging due to a long generation interval, seasonal reproduction, and lack of records and pedigrees.

Genome-Wide Diversity, Population Structure and Demographic History of Dromedaries in the Central Desert of Iran.

The development of camel husbandry for good production in a desert climate is very important, thus we need to understand the genetic basis of camels and give attention to genomic analysis. We assessed genome-wide diversity, linkage disequilibrium (LD), effective population size (Ne) and relatedness in 96 dromedaries originating from five different regions of the central desert of Iran using genotyping-by-sequencing (GBS). A total of 14,522 Single Nucleotide Polymorphisms (SNPs) with an average minor allele frequency (MAF) of 0.19 passed quality control and filtering steps. The average observed heterozygosity in the population was estimated at 0.25 ± 0.03. The mean of LD at distances shorter than 40 kb was low (r2 = 0.089 ± 0.234). The camels sampled from the central desert of Iran exhibited higher relatedness than Sudanese and lower than Arabian Peninsula dromedaries. Recent Ne of Iran's camels was estimated to be 89. Predicted Tajima's D (1.28) suggested a bottleneck or balancing selection in dromedary camels in the central desert of Iran. A general decrease in effective and census population size poses a threat for Iran's dromedaries. This report is the first SNP calling report on nearly the chromosome level and a first step towards understanding genomic diversity, population structure and demography in Iranian dromedaries.