First Report of a Derivative Chromosome 13 with a Duplicated 11p15 Locus Associated with Silver-Russell Syndrome.

Silver-Russell Syndrome (SRS) is a disorder that is primarily characterised by intrauterine growth restriction which may occur asymmetrically or in whole, leading to a fetus being small relative to its gestational age. We present a female infant (proband) born in 2018 at a tertiary hospital in Muscat, Oman, with severe congenital anomalies. The proband carried a >25Mb duplication of the chromosomal 11p15-11pter locus of chromosome 13; creating a derivative chromosome 13 (der[13]) and was reported as 46,XX,der(13)add(11p15-11pter). A methylation-sensitive assay confirmed a diagnosis of SRS. Although the prognosis for SRS patients is generally good, the proband presented with a clinically severe phenotype culminating in death at the age of nine months. To the best of the authors' knowledge, this is the first report of a derivative chromosome 13 with a duplicated 11p15 locus in a patient with SRS.

Spondylo-ocular Syndrome Due to a Novel Variant in XYLT2 in an Omani Patient.

Spondylo-ocular syndrome (SOS) is a rare autosomal recessive disorder and affects primarily ocular and spinal tissues. This case report presented an Omani child with a novel homozygous variant, c.2070 G > A (p.Trp690Ter) in XYLT2 associated with SOS for the first time. Oman and other Middle East countries have a high consanguine marriage rate. Our case report will increase knowledge of SOS syndrome to be able to provide genetic diagnosis and counseling for other family members and families as well as prenatal diagnostics for the future pregnancies.

A Novel SPINK5 Gene Mutation Associated with Netherton Syndrome in an Omani Patient.

Netherton syndrome (NS) is an autosomal recessive primary immunodeficiency. It is characterised by substantial skin barrier defects and is often misdiagnosed as severe atopic dermatitis or hyper-immunoglobulin E syndrome. Although more than 80 NS-associated pathogenic mutations in the serine peptidase inhibitor kazal type 5 (SPINK5) gene have been reported worldwide, only one has been reported in the Arab population to date. We report the case of a novel association between the c.1887+1G>A mutation in the SPINK5 gene and NS in an Omani-Arab patient born in 2014 who was managed at a paediatric immunology clinic in Muscat, Oman. Accurate genetic diagnosis facilitated tailored clinical management of the index patient and enabled the provision of genetic counselling and offering of future reproductive options to the individuals related to the index patient.

Hereditary Paraganglioma in an Omani Family.

Pheochromocytomas are tumors derived from chromaffin cells within the medulla of adrenal glands, whereas paragangliomas are tumors derived from extra-adrenal chromaffin cells of the sympathetic prevertebral and paravertebral ganglia. The growing deployment of genetic testing has shown that approximately 30% of pheochromocytoma and paraganglioma (PPGL) patients carry familial pathogenic germline mutations in known PPGL-susceptibility genes. This prompts genetic screening of their family members and leads to an increase in the detection of asymptomatic PPGLs or non-secreting tumors reported in familial cases discovered after the index patient work-up. Here, we present three case reports of affected members of a single Omani family with a history of paraganglioma and highly variable clinical presentations among the affected members. Eight out of the 16 siblings (50.0%) in the second generation of the reported family pedigree were carriers of the succinate dehydrogenase B:c.574T>C mutation, reflecting the autosomal dominant inheritance risk of paraganglioma and other associated tumors. This report highlights the complexity of managing such families and encourages further discussion regarding the management of asymptomatic PPGL-associated mutation carriers. Genetic screening has enabled the early detection of PPGLs, for which early surgical intervention can significantly impact prognosis and treatment strategies to reduce morbidity and mortality. Although PPGLs are similar tumors, they warrant distinction from each other with respect to their differences in locations, manifestations, secretory functions, genetic syndromes, and propensity to metastasize. While current guidelines are clear concerning symptomatic PPGL cases, the management of asymptomatic mutation carriers requires further elucidation.

A first case report of hypohidrotic ectodermal dysplasia from Oman.

This is a first case report of a patient with hypohidrotic ectodermal dysplasia from Oman, who was found to carry a mutation in the EDAR gene after candidate gene selection based on regions of homozygosity in his genome.

Rare NF1 microdeletion syndrome in an Omani patient.

Neurofibromatosis-1 phenotype combined with webbed neck and short stature in a young Omani patient was revealed to be due to a de novo germ-line heterozygous 1.7 Mb microdeletion at 17q11.2. This lead to the diagnosis of NF1 microdeletion syndrome.

Genetic mutations associated with neonatal diabetes mellitus in Omani patients.

BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare disorder worldwide where diabetes is diagnosed in the first 6 months of life. However, Oman has a relatively high incidence of NDM. METHODS: In this study, we investigated the genetic etiologies underlying NDM and their prevalence in Oman. We collected a cohort of 24 NDM patients, with and without genetic diagnosis, referred to our center from 2007 to 2015. All patients without a genetic diagnosis were tested for mutations in 23 NDM-associated genes using a custom-targeted next-generation sequencing (NGS) panel and methylation analysis of the 6q24 locus. RESULTS: A genetic abnormality was detected in 15/24 (62.5%) of our Omani NDM patients. We report the detection of 6q24 methylation abnormalities and KCNJ11 mutations for the first time in Omani NDM patients. Unlike Western populations where NDM is predominantly due to mutations in the KCNJ11, ABCC8 and INS genes, NDM due to homozygous GCK gene mutations were most prevalent in Oman, having been observed in seven out of 15 NDM patients in whom we established the genetic etiology. This reflects the high degree of consanguinity which makes recessive conditions more likely. CONCLUSIONS: The results of this study are likely to impact any future strategy to introduce genetic testing for NDM disorders within the national healthcare system in Oman.

Repository of mutations from Oman: The entry point to a national mutation database.

The Sultanate of Oman is a rapidly developing Muslim country with well-organized government-funded health care services, and expanding medical genetic facilities. The preservation of tribal structures within the Omani population coupled with geographical isolation has produced unique patterns of rare mutations. In order to provide diagnosticians and researchers with access to an up-to-date resource that will assist them in their daily practice we collated and analyzed all of the Mendelian disease-associated mutations identified in the Omani population. By the 1 (st) of August 2015, the dataset contained 300 mutations detected in over 150 different genes. More than half of the data collected reflect novel genetic variations that were first described in the Omani population, and most disorders with known mutations are inherited in an autosomal recessive fashion. A number of novel Mendelian disease genes have been discovered in Omani nationals, and the corresponding mutations are included here. The current study provides a comprehensive resource of the mutations in the Omani population published in scientific literature or reported through service provision that will be useful for genetic care in Oman and will be a starting point for variation databases as next-generation sequencing technologies are introduced into genetic medicine in Oman.

Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glands of primary Sjögren's syndrome patients.

In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren's syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36-52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients' parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.

B-cell populations and sub-populations in Sjögren's syndrome.

Sjögren's Syndrome (SS) is a chronic inflammatory disorder affecting exocrine glands, in particular the lacrimal and salivary glands. The disease can be primary (pSS) or secondary to other systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and others. The systemic autoimmune character of pSS is also apparent from the occurrence of (non-organ specific) autoantibodies in this disease. Histopathologically, glandular involvement is characterized by focal accumulation of lymphocytes, particularly around epithelial ducts, with, sometimes, germinal center-like structures. The infiltrates largely consist of T-cells, with a preponderance of CD4-positive T-cells. As a result, the pathology in SS was primarily attributed to T cells. However, a break with the fixation on the role of T cells in pSS came when therapeutic B-cell depletion strategies proved remarkably efficacious in this disease, thereby indicating a major role for B-cells in the immunopathogenesis of pSS. In this regard, a closer look at the composition of B-cells and B-cell sub-populations, both in the peripheral blood and in target tissues, is worthwhile. In this review, we discuss current data on B-cells in pSS. B-cell depletion offers a unique possibility to study the recurrence of (pathogenic) B-cells and their characteristics in pSS patients treated with rituximab. Data on B-cell sub-populations in the peripheral blood and B-cell repertoire in the target tissues following rituximab treatment are discussed as well. We also address their state of activation, repertoire, and relation to B-cell activating factor (BAFF).

Persistence of immunoglobulin-producing cells in parotid salivary glands of patients with primary Sjögren's syndrome after B cell depletion therapy.

OBJECTIVES: To assess the persistence of immunoglobulin-producing cell populations in the parotid salivary glands of patients with primary Sjögren's syndrome (pSS) after B cell depletion therapy with rituximab. METHODS: Thirteen patients with pSS and four control patients were included in this study. Patients with pSS were treated with rituximab or placebo. Sequence analysis was carried out on IgA- and IgG-encoding transcripts extracted from parotid salivary gland biopsy specimens taken before treatment and at 12-16 and 36-52 weeks after treatment. RESULTS: At baseline, many clonally related sequences were seen in patients with pSS. The number of clonal expansions was significantly higher in patients with pSS than in control patients. Clonal expansions were composed of IgA- and/or IgG-expressing cells. Rituximab did not significantly alter the degree of clonal expansions. Groups of clonally related cells had members which were shared between biopsy specimens taken before and after treatment. Mutation frequencies of immunoglobulin sequences from clonally related cells in patients with pSS were higher after treatment. CONCLUSIONS: Rituximab treatment does not alter the characteristic features of increased clonal expansions seen in the parotid salivary glands of patients with pSS. The presence of clonally related immunoglobulin-producing cells before and after rituximab treatment strongly suggests that immunoglobulin-producing cells persist in salivary glands of patients with pSS despite B cell depletion. The presence of mixed isotype expression within groups of clonally related cells indicates local class switching in salivary glands of patients with pSS. Persistent immunoglobulin-producing cells may underlie disease relapse after treatment.