Molecular and Clinical Characterization of a Cohort of Autosomal Recessive Sensorineural Hearing Loss in Egyptian Patients.

Hearing loss (HL) is one of the most common health problems worldwide. Autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL) represents a large portion of congenital hereditary HL. Our study was conducted on 13 patients from 13 unrelated families.

Clinical and Molecular Profiles of a Cohort of Egyptian Patients with Collagen VI-Related Dystrophy.

Collagen VI-related dystrophies (COL6-RD) display a wide spectrum of disease severity and genetic variability ranging from mild Bethlem myopathy (BM) to severe Ullrich congenital muscular dystrophy (UCMD) and the intermediate severities in between with dual modes of inheritance, dominant and recessive. In the current study, next-generation sequencing demonstrated potential variants in the genes coding for the three alpha chains of collagen VI (COL6A1, COL6A2, or COL6A3) in a cohort of Egyptian patients with progressive muscle weakness (n = 23). Based on the age of disease onset and the patient clinical course, subjects were diagnosed as follows: 12 with UCMD, 8 with BM, and 3 with intermediate disease form.

Pathogenic variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast () and TnI-slow (), are predominantly expressed in fast- and slow-twitch myofibers, respectively. variants are a rare cause of arthrogryposis, whereas variants have not been conclusively established to cause skeletal myopathy.

Expanding the phenotypic spectrum of LHCGR signal peptide insertion variant: novel clinical and allelic findings causing Leydig cell hypoplasia type II.

Purpose: Leydig cell hypoplasia (LCH) type II is a rare disease with only a few cases reported. Patients presented with hypospadias, micropenis, undescended testes, or infertility. In this study, we report a new patient with compound heterozygous variants in the LHCGR gene and LCH type II phenotype.

Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS.

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs.

Mutation analysis reveals novel and known mutations in SAG gene in first two Egyptian families with Oguchi disease.

Background: Oguchi disease is a rare type of congenital stationary night blindness associated with an abnormal fundus appearance. It is inherited in an autosomal recessive manner where two types exist according to the gene affected; type 1 associated with S-antigen (SAG) gene mutations and type 2 associated with rhodopsin kinase (GRK1) gene mutations.

Purpose: The aim of this work was to describe the clinical and genetic findings of the first two reported families of Oguchi disease in Egypt and African region.

First Report of Two Egyptian Patients with Desbuquois Dysplasia due to Homozygous Mutations.

Desbuquois dysplasia type 1 (DBQD1) is a very rare skeletal dysplasia characterized by growth retardation, short stature, distinct hand features, and a characteristic radiological monkey wrench appearance at the proximal femur. We report on 2unrelated Egyptian patients having the characteristic features of DBQD1 with different expressivity. Patient 1 presented at the age of 45 days with respiratory distress, short limbs, faltering growth, and distinctive facies while patient 2 presented at 5 years of age with short stature and hypospadias.

Quaternary diagnostics scheme for mucolipidosis II and detection of novel mutation in GNPTAB gene.

Background: Mucolipidosis II (ML II α/β) is an inherited lysosomal storage disorder caused by deficiency of GlcNAc-phosphotransferase enzyme and results in mis-targeting of multiple lysosomal enzymes. Affected patients are characterized by skeletal deformities and developmental delay. Homozygous or compound heterozygous mutations in GNPTAB gene are associated with the clinical presentation.

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development.

Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three-year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt.

Impact of miRNAs expression modulation on the methylation status of breast cancer stem cell-related genes.

Purpose: Altered miRNAs play a crucial role in the emergence of the breast cancer stem cell (BCSC) phenotype. The interplay between miRNAs and methylation enzymes has been documented. One of the most aggressive breast cancer cell lines, MDA-MB-231, has expressed much more DNMT3B than DNMT3A.

Potential Value of miR-23a for Discriminating Neuromyelitis Optica Spectrum Disorder from Multiple Sclerosis.

Background: Until now, no laboratory test or test set can guarantee the diagnosis of multiple sclerosis (MS) at early disease stages, and the disease symptoms may interfere with many other disease conditions. Analyzing the expression of circulating miRNAs may provide a useful approach for early and differential MS diagnosis. The main objective is assessment of the potential of serum miR-23a, miR-155, and miR-572 to differentiate between MS and other neuroinflammatory diseases.

Novel mutations of the LHCGR gene in two families with 46,XY DSD causing Leydig cell hypoplasia I.

Purpose: Leydig cell hypoplasia is a rare autosomal recessive 46,XY disorder of sexual development (DSD). It is caused by homozygous or compound heterozygous inactivating mutations in the human luteinizing hormone/chorionic gonadotropin hormone receptor (LHCGR) gene. In Leydig cell hypoplasia type I, patients are characterized by predominantly female external genitalia, which usually go unrecognized until the age of puberty.

Assessment of the most common CYP21A2 point mutations in a cohort of congenital adrenal hyperplasia patients from Egypt.

Objectives Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by defects in the CYP21A2 gene. We aimed to determine the prevalence of the most commonly reported mutations among 21-OHD Egyptian patients and correlate genotype with phenotype. Methods Molecular analysis of the CYP21A2 gene was performed for the detection of the six most common point mutations (p.

WT1 Gene Mutation, p.R462W, in a 46,XY DSD Patient from Egypt with Gonadoblastoma and Review of the Literature.

WT1 gene mutations have been described in 46,XY patients with ambiguous genitalia or complete gonadal dysgenesis with or without Wilms' tumor, nephropathy, gonadoblastoma, and other defects, e.g., cryptorchidism or hypospadias.

Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases.

Background: Although misdiagnosis of neuromyelitis optica spectrum disorder (NMOSD) with neuropsychiatric systemic lupus erythematosus (NPSLE) or multiple sclerosis (MS) is not infrequent, reliable biomarkers remains an unmet need. Extracellular microRNAs (miRNAs) represent a worthy avenue to identify biomarkers for differential diagnosis. We aimed to explore the potential role of some selected circulating miRNAs as biomarkers for the differential diagnosis in immune-mediated neuroinflammatory diseases.

Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients.

Background: Mutations in the HSD17B3 gene are associated with a 46,XY disorder of sexual development (46,XY DSD) as a result of low testosterone production during embryogenesis.

Aim: To elucidate the molecular basis of the disorder by chemically analyzing four missense mutations in HSD17B3 (T54A, M164T, L194P, G289S) from Egyptian patients with 46,XY DSD.

Methods: Expression plasmids for wild-type 17β-hydroxysteroid hydrogenase type 3 (17β-HSD3) and mutant enzymes generated by site-directed mutagenesis were transiently transfected into human HEK-293 cells.

Four novel mutations in the N-acetylgalactosamine-6-sulfate sulfatase gene among Egyptian patients with Morquio A disease.

Morquio A disease (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS) encoded by the GALNS gene. This deficiency leads to a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing their accumulation within the lysosomes and consequently prominent skeletal and visceral abnormalities. Clinical evaluation and biochemical GALNS enzyme activity determination were carried out for the patients from four unrelated Egyptian families.

Identification of NR5A1 Mutations and Possible Digenic Inheritance in 46,XY Gonadal Dysgenesis.

The phenotypic spectrum of patients carrying NR5A1 mutations ranges from 46,XY gonadal dysgenesis to male infertility. Phenotypic variability could be due to digenic or oligogenic inheritance of pathogenic variants in other testis-determining genes. Here, exome sequencing identified 2 pathogenic de novo NR5A1 mutations in 2 patients with 46,XY gonadal dysgenesis, p.

Mutational Profile of 10 Afflicted Egyptian Families with 17-β-HSD-3 Deficiency.

This study aimed at the detection of HSD17B3 gene mutations in Egyptian patients with suspected diagnosis of 46,XY DSD due to 17-β-HSD-3 deficiency and at evaluation of phenotype/genotype relationship of these mutations. The study was conducted on 11 patients of 10 families which were provisionally diagnosed to have 17-β-HSD-3 enzyme deficiency. Karyotyping, hormonal evaluation of testosterone, x0394;4-androstenedione, and dihydrotestosterone, and sequencing analysis of the 11 exons of the HSD17B3 gene were done.

ROBERTS SYNDROME: CLINICAL AND CYTOGENETIC STUDIES IN 8 EGYPTIAN PATIENTS AND MOLECULAR STUDIES IN 4 PATIENTS WITH GENOTYPE/PHENOTYPE CORRELATION.

The Roberts syndrome (RBS) is a rare autosomal recessive disorder caused by mutation in ESCO2 gene. Among over 150 reported international cases, 16 cases are Egyptian including the presently reported patients. The current study reports 8 new Egyptian patients from 7 unrelated consanguineous families investigating clinical phenotype as well as cytogenetic changes in all cases and mutational spectrum in 4 cases.

Circulating miRNAs 21 and 221 as biomarkers for early diagnosis of prostate cancer.

To compare the expression of two promising circulating micro-ribonucleic acids (miRNAs 21 and 221) in patients with prostate cancer to subjects without cancer and to evaluate their potential role as specific noninvasive molecular biomarkers for prostate cancer diagnosis, circulating miRNAs 21 and 221 expression profiles were analyzed in 20 men aged 50-75 years, presenting with lower urinary tract symptoms (LUTSs) and undergoing transrectal ultrasound (TRUS)-guided prostate biopsy based on either elevated serum prostate-specific antigen (PSA) (>4.0 ng/ml) or suspicious digital rectal examination (DRE). The performance of miRNAs 21 and 221 in differentiating prostate cancer from nonmalignant cases was evaluated and compared to DRE and elevated PSA.

A novel mutation (c.2735_2736delTC) in the androgen receptor gene in 46,XY females with complete androgen insensitivity syndrome in an Egyptian family.

Background: Androgen insensitivity syndrome (AIS) results from resistance of the target tissues to the effect of the androgenic hormones producing a phenotype with varying degrees of feminization ranging from male infertility to completely normal female external genitalia. Androgen receptor (AR) is a transcription factor that interacts with the androgenic steroids that act as ligands activating the AR, and via different cellular mechanisms, the activated AR binds to the DNA of target tissues to induce the desired biological changes. To date, more than 800 different mutations in the AR gene have been identified in patients with AIS and the majority of these mutations are localized in the ligand-binding domain.

Mutational analysis of the PTPN11 gene in Egyptian patients with Noonan syndrome.

Background/purpose: Noonan syndrome (NS) is inherited as an autosomal dominant disorder with dysmorphic facies, short stature, and cardiac defects, which can be caused by missense mutations in the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene, which encodes src homology region 2 domain containing tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase that acts in signal transduction downstream to growth factors and cytokines. The current study aimed to study the molecular characterization of the PTPN11 gene among Egyptian patients with Noonan syndrome.

Methods: Eleven exons of the PTPN11 gene were amplified and screened by single stranded conformational polymorphism (SSCP).

A novel nonsense mutation in exon 1 of HSD17B3 gene in an Egyptian 46,XY adult female presenting with primary amenorrhea.

17-β-Hydroxysteroid dehydrogenase type 3 deficiency is a rare autosomal recessive cause of 46,XY disorder of sex development. Worldwide, about 30 mutations in the hydroxysteroid (17-beta) dehydrogenase 3 (HSD17B3) gene have been reported, involving all exons except exon 1. Herein, we investigated an Egyptian female with 46,XY karyotype and low testosterone/Δ4-androstenedione ratio.

Unique karyotype: mos 46,X,dic(X;Y)(p22.33;p11.32)/ 45,X/45,dic(X;Y)(p22.33;p11.32) in an Egyptian patient with Ovotesticular disorder of sexual development.

Ovotesticular disorder of sexual development (OT-DSD) is an unusual form of DSD, characterized by the coexistence of testicular and ovarian tissue in the same individual. In this report, we present clinical, cytogenetic and molecular data of an Egyptian patient with ambiguous genitalia and OT-DSD, who had a unique karyotype comprising 3 different cell lines: mos 46,X,dic(X;Y)(p22.33;p11.