Detecting Causal Variants in Mendelian Disorders Using Whole-Genome Sequencing.

Increasingly affordable sequencing technologies are revolutionizing the field of genomic medicine. It is now feasible to interrogate all major classes of variation in an individual across the entire genome for less than $1000 USD. While the generation of patient sequence information using these technologies has become routine, the analysis and interpretation of this data remains the greatest obstacle to widespread clinical implementation.

Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in .

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections.

Association of Myoinositol Transporters with Schizophrenia and Bipolar Disorder: Evidence from Human and Animal Studies.

Evidence from animal and human studies has linked -inositol (MI) with the pathophysiology and/or treatment of psychiatric disorders such as schizophrenia and bipolar disorder. However, there is still controversy surrounding the definitive role of MI in these disorders. Given that brain MI is differentially regulated by three transporters - SMIT1, SMIT2 and/or HMIT (encoded by the genes: , and , respectively) - we used available datasets to describe the distribution in mouse and human brain of the different MI transporters and to examine changes in mRNA expression of these transporters in patients with schizophrenia and bipolar disorder.

Melanin Concentrating Hormone Signaling Deficits in Schizophrenia: Association With Memory and Social Impairments and Abnormal Sensorimotor Gating.

Background: Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association.

Methods: We analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls.

Expanded PCH1D phenotype linked to EXOSC9 mutation.

Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.

Identification of a novel homozygous UNC80 variant in a child with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2).

The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report on a novel homozygous mutation in UNC80 in a Palestinian-Emirati patient suffering infantile hypotonia with psychomotor retardation and characteristic facies. This mutation was detected by whole exome sequencing and confirmed using Sanger sequencing in the patient-parents trio.

Novel PDE6A mutation in an Emirati patient with retinitis pigmentosa.

Mutations in the PDE6A gene are known to cause a form of retinitis pigmentosa (RP43), characterized by progressive retinal degeneration. We describe an Emirati patient with RP caused by a novel mutation in PDE6A. Clinical diagnosis of RP was made based on clinical evaluation and electroretinograms.

Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs.

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups.

Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report.

Background: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor.

Summary of mutations underlying autosomal recessive congenital ichthyoses (ARCI) in Arabs with four novel mutations in ARCI-related genes from the United Arab Emirates.

Background: Clinical and molecular heterogeneity is a prominent characteristic of congenital ichthyoses, with the involvement of numerous causative loci. Mutations in these loci feature in autosomal recessive congenital ichthyoses (ARCIs) quite variably, with certain genes/mutations being more frequently uncovered in particular populations.

Methods: In this study, we used whole exome sequencing as well as direct Sanger sequencing to uncover four novel mutations in ARCI-related genes, which were found in families from the United Arab Emirates.

A Novel Variant in the Endothelin-Converting Enzyme-Like 1 (ECEL1) Gene in an Emirati Child.

Objective: The aim of this work was to report a case of an Emirati child who presented with developmental delay and multiple congenital abnormalities that are consistent with distal arthrogryposis type 5D.

Clinical Presentation And Intervention: The clinical presentation comprised contractures of the shoulders, elbows, and knees in addition to camptodactyly and neck pterygium. The facial dysmorphic features noted include ptosis and microretrognathia.

A novel, putatively null, FGD1 variant leading to Aarskog-Scott syndrome in a family from UAE.

Background: The X-linked condition "Aarskog-Scott syndrome (AAS)" causes a characteristic combination of short stature, facial, genital and skeletal anomalies. Studies elucidated a causative link between AAS and mutations in the FGD1 gene, which encodes a Rho/Rac guanine exchange factor. FGD1 is involved in regulating signaling pathways that control cytoskeleton organization and embryogenesis.

Marinesco-Sjögren Syndrome in an Emirati Child with a Novel Mutation in SIL1 Affecting the 5' Untranslated Region.

Objective: The aim of this study was to report clinical and molecular findings in an Emirati child with Marinesco-Sjögren syndrome born to consanguineous parents.

Clinical Presentation And Intervention: The child presented with developmental delay, ataxia, bilateral cataracts, and dysmorphic craniofacial features, along with cerebellar atrophy. Sequencing of the SIL1 gene revealed a novel homozygous large indel mutation that was predicted to abrogate part of the 5' untranslated region (UTR) and the first 30 amino acids of the protein.

Meta-analyses of the association of HLA-DRB1 alleles with rheumatoid arthritis among Arabs.

Aim: Various studies incorporating Arab populations have reported on specific associations between HLA-DRB1 variants and rheumatoid arthritis (RA). We sought to provide an overview on the association of HLA-DRB1 with RA in Arabs using meta-analysis tools.

Methods: Data on allele counts and frequencies were compiled from the relevant literature (published before 16 February 2016) and the associations of 13 -DRB1 variants with RA were assessed; relationships were defined in terms of odds ratios (ORs) with a 95% confidence interval.

Identification of a Novel Homozygous INSR Variant in a Patient with Rabson-Mendenhall Syndrome from the United Arab Emirates.

Background/aims: This study aimed to identify, clinically and molecularly, the causality of Rabson-Mendenhall syndrome in an Emirati family. It is one of the monogenic syndromes of abnormal glucose homeostasis, which result from insulin receptor defects.

Methods: A novel nonsynonymous variant in the INSR gene was uncovered by whole exome sequencing and confirmed using Sanger sequencing in the patient and his parents.

Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation.

Microcephaly is a rare neurological condition, both in isolation and when it occurs as part of a syndrome. One of the syndromic forms of microcephaly is microcephaly, seizures and developmental delay (MCSZ) (OMIM #613402), a rare autosomal recessive neurodevelopmental disorder with a range of phenotypic severity, and known to be caused by mutations in the polynucleotide kinase 3' phosphatase (PNKP) gene. The PNK protein is a key enzyme involved in the repair of single and double stranded DNA breaks, a process which is particularly important in the nervous system.

Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis.

ECHS1 is a mitochondrial matrix enzyme that catalyzes an important step in the β-oxidation spiral of fatty acid catabolism, and individuals with mutations in the ECHS1 gene suffer from an autosomal recessive condition typified by delayed psychomotor development, mitochondrial encephalopathy, hypotonia, and cardiomyopathy. Here we report the first Arab case of ECHS1 Deficiency. The patient was born to consanguineous parents with all growth parameters being low for gestational age, and was persistently desaturated.

A novel nonsense GPSM2 mutation in a Yemeni family underlying Chudley-McCullough syndrome.

Mutations in the G Protein Signaling Modulator 2 (GPSM2) cause the autosomal recessive disorder Chudley-McCullough syndrome (CMS), which is characterized by profound congenital sensorineural hearing loss with various abnormalities in the brain. This phenotypic combination is attributed to the role played by GPSM2 in the establishment of planar polarity and spindle orientation during asymmetric cell divisions. Here we present two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing.

Genetics of multifactorial disorders: proceedings of the 6th Pan Arab Human Genetics Conference.

The 6th Pan Arab Human Genetics Conference (PAHGC), "Genetics of Multifactorial Disorders" was organized by the Center for Arab Genomic Studies (http://www.cags.org.

A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome by Whole Exome Sequencing.

The SOX18 gene encodes a transcription factor that plays a notable role in certain developmental contexts such as lymphangiogenesis, hair follicle development and vasculogenesis. SOX18 mutations are linked to recessive and dominant hypotrichosis-lymphedema-telangiectasia syndrome (HLTS). In this study we report on a novel heterozygous mutation in SOX18 in a Jordanian patient suffering from HLTS that was revealed by Whole Exome Sequencing.

Novel splice-site mutation in WDR62 revealed by whole-exome sequencing in a Sudanese family with primary microcephaly.

The WDR62 gene encodes a scaffold protein of the c-Jun N-terminal kinase (JNK) pathway. It plays a critical role in laying out various cellular layers in the cerebral cortex during embryogenesis, and hence the dramatic clinical features resulting from WDR62 mutations. These mutations are associated with autosomal recessive primary microcephaly 2, with or without cortical malformations (MCPH2).