Predicting Consanguinity Rates from Exome Sequencing Data in the Lebanese Population.

Consanguinity, prevalent in certain populations because of cultural and social factors, significantly increases the risk of genetic autosomal recessive disorders. In Lebanon, consanguineous marriages constitute 35.5% of unions, with first cousin marriages being the most common.

Endophilin A2 Deficiency Impairs Antibody Production in Humans.

Endophilin A2, the sole endophilin A family member expressed in hematopoietic cells, regulates various aspects of membrane dynamics, including autophagy and endocytosis. Recent studies in rodents highlight the essential role of endophilin A2 in modulating immune responses. Here we report a homozygous frameshift variant in the SH3GL1 gene (NM_003025.

POLD3 haploinsufficiency is linked to non-syndromic sensorineural adult-onset progressive hearing and balance impairments.

Hearing impairment (HI) is a significant health concern globally, influenced by genetic and environmental factors. We had identified a homozygous pathogenic variant in POLD3 in a Lebanese patient with an autosomal congenital recessive syndromic hearing loss (MIM#620869). This variant was found at heterozygous state in the parents, who developed progressive hearing impairment around age 40.

Expanding the phenotypes of ABL1 deficiency syndromes: When mutations in different isoforms Lead to different diseases.

All reported ABL1 gain of function and loss of function (LOF) variants, impact both isoforms 1a and 1b. Our findings suggest that LOF variants affecting solely ABL1 isoform 1b may lead to a distinct autosomal recessive new phenotype.

CNV Analysis through Exome Sequencing Reveals a Large Duplication Involved in Sex Reversal, Neurodevelopmental Delay, Epilepsy and Optic Atrophy.

Background: Duplications on the short arm of chromosome X, including the gene , have been associated with gonadal dysgenesis and with male to female sex reversal. Additional clinical manifestations can be observed in the affected patients, depending on the duplicated genomic region. Here we report one of the largest duplications on chromosome X, in a Lebanese patient, and we provide the first comprehensive review of duplications in this genomic region.

How many phenotypes for the FBXO11 related disease? Report on a new patient with a tricho-rhino-phalangeal like phenotype.

Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.

A homozygous frameshift variant expands the clinical spectrum of SAMD9 gene defects.

SAMD9, a ubiquitously expressed protein, is involved in several mechanisms, including endosome fusion, growth suppression and modulation of innate immune responses to stress and viral infections. While biallelic mutations in SAMD9 are linked to normophosphatemic familial tumoral calcinosis, heterozygous gain-of-function mutations in the same gene are responsible for MIRAGE, a multisystemic syndrome characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. A two-and-a-half-year-old girl, from a consanguineous Lebanese family, was included in this study.

Analysis of G-quadruplex forming sequences in podocytes-marker genes and their potential roles in inherited glomerular diseases.

Nephrotic Syndrome is the most widespread pediatric kidney disorder. Genetic alterations in podocyte genes are thought to be responsible for the disease. G-quadruplexes are non-conventional guanine-rich DNA and RNA structures, which are commonly found in regulatory regions.

G-quadruplex forming sequences in the genes coding for cytochrome P450 enzymes and their potential roles in drug metabolism.

The majority of drugs are metabolized by cytochrome P450 (CYP) enzymes, primarily belonging to the CYP1, CYP2 and CYP3 families. Genetic variations are the main cause of inter-individual differences in drug response, which constitutes a major concern in pharmacotherapy. G-quadruplexes (G4s), are non-canonical DNA and RNA secondary structures formed by guanine-rich sequences.

-Related Disorder: Sharing 20 Years of thorough Clinical Follow-Up and Review of the Literature.

Intellectual disability (ID) is a prevalent neurodevelopmental disorder characterized by limitations in intellectual functioning and adaptive behavior. While the causes of ID are still largely unknown, it is believed to result from a combination of environmental exposures and genetic abnormalities. Recent advancements in genomic studies and clinical genetic testing have identified numerous genes associated with neurodevelopmental disorders (NDDs), including ID.

Report on a Case with Moreno-Nishimura-Schmidt Overgrowth Syndrome: A Clinically Delineated Disease Yet of an Unknown Origin!

Introduction: Overgrowth syndromes are a heterogeneous group of genetic disorders characterized by excessive growth, often accompanied by additional clinical features, such as facial dysmorphism, hormonal imbalances, cognitive impairment, and increased risk for neoplasia. Moreno-Nishimura-Schmidt (M-N-S) overgrowth syndrome is a very rare overgrowth syndrome characterized by severe pre- and postnatal overgrowth, dysmorphic facial features, kyphoscoliosis, large hands and feet, inguinal hernia, and distinctive skeletal features. The clinical and radiological features of the disorder have been well delineated, yet its molecular pathogenesis remains unclear.

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment.

Combined immunodeficiency diseases (CID) represent the most severe forms of inborn errors of immunity. Defective T cell development and/or function, leading to an impairment in adaptive immunity are responsible for these diseases. The DNA polymerase δ complex is important for genome duplication and maintenance and consists of the catalytic subunit POLD1, and the accessory subunits POLD2 and POLD3 which stabilizes the complex.

Non-syndromic hypotrichosis: A report of two novel variants in the LSS gene.

To date, more than 15 genes have been linked to syndromic and non-syndromic hypotrichosis, among which the LSS gene encoding lanosterol synthase was recently linked to autosomal recessive isolated hypotrichosis. Here we report the case of a 6-year-old girl born to non-consanguineous Iraqi parents and presenting with sparse lanugo hair since birth on the scalp, eyelashes, and eyebrows. Whole exome sequencing followed by Sanger sequencing allowed the detection of two novel compound heterozygous variants in LSS (p.

in Males: Are Hemizygous Variants Linked to Autism?

Background: Autism spectrum disorder (ASD) is a complex developmental disability that impairs the social communication and interaction of affected individuals and leads to restricted or repetitive behaviors or interests. ASD is genetically heterogeneous, with inheritable and de novo genetic variants in more than hundreds of genes contributing to the disease. However, these account for only around 20% of cases, while the molecular basis of the majority of cases remains unelucidated as of yet.

BHLHA9 homozygous duplication in a consanguineous family: A challenge for genetic counseling.

Split-hand/foot malformation (SHFM) with long-bone deficiency (SHFLD) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. It includes three different types; SHFLD1 (MIM % 119,100), SHFLD2 (MIM % 610,685) and SHFLD3 (MIM # 612576). The latter was shown to be the most commonly reported with a duplication in the 17p13.

The Middle East and North Africa Diagnosis and Management Guidelines for Inborn Errors of Immunity.

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders.

New complementary python codes to locate Single Nucleotide Polymorphisms (SNPs) and Overlapping G-Quadruplex Sequences (G4s).

G-quadruplexes (G4s) are non-canonical DNA and RNA secondary structures that control gene regulation. A single nucleotide polymorphism (SNP) is a small genetic variation occurring within a DNA sequence and accounting for the variabilities between individuals. While the majority of SNPs, especially those frequent in the population, are considered as benign genetic variations, few others can lead to diseases.

NEK8-Associated Nephropathies: Do Autosomal Dominant Forms Exist?

Introduction: Nephronophthisis (NPHP) is a group of autosomal recessive renal diseases characterized by a reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, and cystic kidney disease. It represents the most common genetic cause of childhood renal failure. To date, around 20 different genes, encoding primary cilia proteins, have been linked to NPHP.

Identification by whole-exome sequencing of new single-nucleotide polymorphisms associated with molar-incisor hypomineralisation among the Lebanese population.

Objective: Molar-incisor hypomineralization (MIH) is a developmental qualitative enamel defect, causing a worldwide challenging dental problem. The etiology of this defect remains unclear. Here we identify by whole-exome sequencing (WES) new single-nucleotide polymorphisms (SNPs) in genes expressed during enamel mineralization and in those modulating prenatal, natal and postnatal risk factors among the Lebanese MIH children: immune system and xenobiotic detoxification.

Early infantile epileptic encephalopathy related to NECAP1: Clinical delineation of the disease and review.

Background And Purpose: Epileptic encephalopathy (EE) refers to a heterogeneous group of epilepsy syndromes characterized by seizures as well as encephalopathies, leading to cognitive and behavioral disturbances. These conditions vary in their age at onset, their severity, and their electroencephalographic patterns. Whereas genetic factors are involved in approximately 40% of all epilepsy cases, they contribute to 80% of early infantile EEs (EIEEs), with approximately 125 genes previously linked to this disease.