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While de novo mutations (DNMs) are key to genetic diversity, they are also responsible for a high number of rare disorders. To date, no study has systematically examined the rate and distribution of DNMs in multiplex families in highly consanguineous populations. Leveraging WGS profiles of 645 individuals in 146 families, we implemented a combinatorial approach using 3 complementary tools for DNM discovery in 353 unique trio combinations. We found a total of 27,168 DNMs (median: 70 single-nucleotide and 6 insertion-deletions per individual). Phasing revealed around 80% of DNMs were paternal in origin. Notably, using whole-genome methylation data of spermatogonial stem cells, these DNMs were significantly more likely to occur at highly methylated CpGs (OR: 2.03; p value = 6.62 × 10−11). We then examined the effects of consanguinity and ethnicity on DNMs, and found that consanguinity does not seem to correlate with DNM rate, and special attention has to be considered while measuring such a correlation. Additionally, we found that Middle-Eastern families with Arab ancestry had fewer DNMs than African families, although not significant (p value = 0.16). Finally, for families with diseased probands, we examined the difference in DNM counts and putative impact across affected and unaffected siblings, but did not find significant differences between disease groups, likely owing to the enrichment for recessive disorders in this part of the world, or the small sample size per clinical condition. This study serves as a reference for DNM discovery in multiplex families from the globally under-represented populations of the Middle-East.Other Information Published in: Journal of Human Genetics License: https://creativecommons.org/licenses/by/4.0See article on publisher's website: http://dx.doi.org/10.1038/s10038-022-01054-9

Item does not contain fulltext Sudan, a northeastern African country, is characterized by high levels of cultural, linguistic, and genetic diversity, which is believed to be affected by continuous migration from neighboring countries. Consistent with such demographic effect, genome-wide SNP data revealed a shared ancestral component among Sudanese Afro-Asiatic speaking groups and non-African populations, mainly from West Asia. Although this component is shared among all Afro-Asiatic speaking groups, the extent of this sharing in Semitic groups, such as Sudanese Arab, is still unknown. Using genotypes of six polymorphic human leukocyte antigen (HLA) genes (i.e., HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1), we examined the genetic structure of eight East African ethnic groups with origins in Sudan, South Sudan, and Ethiopia. We identified informative HLA alleles using principal component analysis, which revealed that the two Semitic groups (Gaalien and Shokrya) constituted a distinct cluster from the other Afro-Asiatic speaking groups in this study. The HLA alleles that distinguished Semitic Arabs co-exist in the same extended HLA haplotype, and those alleles are in strong linkage disequilibrium. Interestingly, we find the four-locus haplotype "C*12:02-B*52:01-DRB1*15:02-DQB1*06:01" exclusively in non-African populations and it is widely spread across Asia. The identification of this haplotype suggests a gene flow from Asia, and likely these haplotypes were brought to Africa through back migration from the Near East. These findings will be of interest to biomedical and anthropological studies that examine the demographic history of northeast Africa.

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental delay, craniofacial malformations such as malar and mandibular hypoplasia, and ear anomalies. Here, we report a 4.5-yr-old female patient with symptoms fitting MFDM. Using whole-genome sequencing, we identified a de novo start-codon loss (c.3GT) in the

Despite recent biomedical breakthroughs and large genomic studies growing momentum, the Middle Eastern population, home to over 400 million people, is underrepresented in the human genome variation databases. Here we describe insights from Phase 1 of the Qatar Genome Program with whole genome sequenced 6047 individuals from Qatar. We identified more than 88 million variants of which 24 million are novel and 23 million are singletons. Consistent with the high consanguinity and founder effects in the region, we found that several rare deleterious variants were more common in the Qatari population while others seem to provide protection against diseases and have shaped the genetic architecture of adaptive phenotypes. These results highlight the value of our data as a resource to advance genetic studies in the Arab and neighboring Middle Eastern populations and will significantly boost the current efforts to improve our understanding of global patterns of human variations, human history, and genetic contributions to health and diseases in diverse populations.

Despite recent biomedical breakthroughs and large genomic studies growing momentum, the Middle Eastern population, home to over 400 million people, is under-represented in the human genome variation databases. Here we describe insights from phase 1 of the Qatar Genome Program which whole genome sequenced 6,045 individuals from Qatar. We identified more than 88 million variants of which 24 million are novel and 23 million are singletons. Consistent with the high consanguinity and founder effects in the region, we found that several rare deleterious variants were more common in the Qatari population while others seem to provide protection against diseases and have shaped the genetic architecture of adaptive phenotypes. Insights into the genetic structure of the Qatari population revealed five non-admixed subgroups. Based on sequence data, we also reported the heritability and genetic marker associations for 45 clinical traits. These results highlight the value of our data as a resource to advance genetic studies in the Arab and neighbouring Middle Eastern populations and will significantly boost the current efforts to improve our understanding of global patterns of human variations, human history and genetic contributions to health and diseases in diverse populations.

Rare deletions and duplications on the long arm of Chromosome 21 have previously been reported in many patients with craniofacial and developmental phenotypes. However, this Down Syndrome Critical Region (DSCR) contains multiple genes, making identifying a single causative gene difficult. Here, we report a case of a boy with bicoronal craniosynostosis, facial dysmorphism, developmental delay, and intellectual impairment who was found by whole genome sequencing to have a homozygous missense mutation in the Single-Minded Homolog 2 (SIM2) gene (c.461 AG, p.Tyr154Cys) within the DSCR. SIM2 encodes an essential bHLH and PAS domain transcription factor expressed during fetal brain development and acts as a master regulator of neurogenesis. This variant is globally very rare, segregates in the family, and is predicted to be highly deleterious by in silico analysis, 3D molecular modeling of protein structure, and functional analysis of zebrafish models. Zebrafish expressing the human SIM2

Purpose. Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency. The extent to which STK4 deficiency impairs immune signaling and host defenses is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C>T, p.Arg291*) found in a pediatric patient by comparing the patient’s innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls.Methods. The genetic etiology was identified by whole genome sequencing and confirmed by Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA and polychromatic flow cytometry. Finally, antibody responses were delinated by ELISA and phage immunoprecipitation-sequencing.Results. The affected patient exhibited partial loss of STK4 expression and complete loss of STK4 function. The patient suffered from recurrent viral and bacterial infections, most notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormalities to the fractions of T-cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient’s whole blood and PBMC samples were reminiscent of dysregulated interferon signaling, impaired T immunity and increased T-cell apoptosis. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B-cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpesvirus antigens.Conclusion. Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

Background: A 46-year-old Qatari female with a BMI of 25kg/m2 presented with hyperglycemia (blood glucose 13.5 mmol/l), hyperinsulinemia (21µU/mL) with elevated levels of HbA1c (10.3mmol/l). Biochemical investigations showed raised serum C-peptide (2.02ng/ml) and triglycerides (2.07mmol/L) and uric acid (104mg/dL), with normal BP. The objective of this case study is to validate this variant found through WGS in insulin receptor (INSR) gene that play a major cause of insulin resistant syndrome with different spectrums. Methods: Structural Variants discovered using custom multi-algorithm pipeline developed and optimized to run on HPC for short-read WGS data. In brief, 10 software packages applied (Breakdancer, Breakseq2, CNVnator, Delly, ERDS, Genomestrip, Manta, Speedseq, Svaba, WHAM), to existing short-read data. SVs annotated using AnnotSV and provides us functionally, regulatory and clinically relevant information. SVs analyzed based on their properties like pli-score, overlaps with known databases and OMIM annotations. This deletion was validated by ddPCR and the molecular docking performed by the autodock suit in order to understand the effect of deletion in the interaction between this receptor and insulin. Results: The patient was identified with 7.2k heterozygous deletion in exon 8 of INSR gene which play an essential role in the formation of extracellular alpha subunits in insulin receptor. molecular docking proved the decrease of catalytic activity of INSR and, hence signaling. Considering this and the phenotypic data from Qatar biobank, the patient developed features of type A insulin resistant syndrome as consequence of persistence hyperinsulinemia. The patient also exhibits severe Deterioration of glucose tolerant even with medication and unfortunately developed nephropathy. Conclusion: We highlighted the power of NGS in precise diagnosis and developing a potential and promising targeted therapeutics. Disclosure A.S. Akil: None. E.A.M. Yassin: None. S. Subash Padmajeya: None. L.A. Jerman: None. A. Fadda: None. W.H.O. Aamer: None. E.E. Aliyev: None. K. Fakhro: None.