ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency.

Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development.

Objective: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree.

Novel missense variants in the gene from a European family with Moyamoya disease.

In this report, we present a European family with six individuals affected with Moyamoya disease (MMD). We detected two novel missense variants in the Moyamoya susceptibility gene , c.12553A>G (p.

Rapid Paediatric Sequencing (RaPS): comprehensive real-life workflow for rapid diagnosis of critically ill children.

Background: Rare genetic conditions are frequent risk factors for, or direct causes of, paediatric intensive care unit (PICU) admission. Such conditions are frequently suspected but unidentified at PICU admission. Compassionate and effective care is greatly assisted by definitive diagnostic information.

Toward personalized medicine in Bardet-Biedl syndrome.

Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet-Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner.

Managing Bardet-Biedl Syndrome-Now and in the Future.

Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies.

DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.

DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes.

Exome sequencing for the differential diagnosis of ciliary chondrodysplasias: Example of a WDR35 mutation case and review of the literature.

Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.

COLEC10 is mutated in 3MC patients and regulates early craniofacial development.

3MC syndrome is an autosomal recessive heterogeneous disorder with features linked to developmental abnormalities. The main features include facial dysmorphism, craniosynostosis and cleft lip/palate; skeletal structures derived from cranial neural crest cells (cNCC). We previously reported that lectin complement pathway genes COLEC11 and MASP1/3 are mutated in 3MC syndrome patients.

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.

Can Surgery for Inflammatory Bowel Disease be Personalized?

Background: In the treatment of Inflammatory Bowel Diseases (IBD) despite advances in medical therapies, surgery has maintained a leading role in the management of complications of the disease, as well as in cases of failure of medical therapy.

Objective: discuss the possible role for a personalization in debated fields of surgical treatment of Crohn's disease and ulcerative colitis.

Conclusions: Surgery has become more and more minimally invasive, struggling for a difficult balance between guidelines and personalized treatment tailored on the single patient's need.

Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia.

Objective: To characterize the underlying genetic and molecular defects in a consanguineous family with lifelong blood disorder manifested with thrombocytopenia (low platelets count) and anemia.

Methods: Genetic linkage analysis, exome sequencing, and functional genomics were carried out to identify and characterize the defective gene.

Results: We identified a novel truncation mutation (p.

Opportunities and technical challenges in next-generation sequencing for diagnosis of rare pediatric diseases.

Rare pediatric diseases are clinically severe with high rates of mortality and morbidity. This paper outlines how next-generation sequencing (NGS) can be used to greatly advance identification of the underlying genetic causes. Areas covered: This manuscript is a blend of evidence obtained from literature searches from PubMed and rare disease related websites, laboratory experience and the author's opinions.

Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency.

Background: Signaling through the T-cell receptor (TCR) is critical for T-cell development and function. Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells.

Objective: We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers.

Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity.

Seizures Due to a KCNQ2 Mutation: Treatment with Vitamin B6.

There is increasing evidence that vitamin B6, given either as pyridoxine or pyridoxal 5'-phosphate, can sometimes result in improved seizure control in idiopathic epilepsy. Whole-exome sequencing was used to identify a de novo mutation (c.629G>A; p.

The use of whole-exome sequencing to disentangle complex phenotypes.

The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature.

STAG3 truncating variant as the cause of primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development.

Variable phenotype of severe immunodeficiencies associated with RMRP gene mutations.

Purpose: Mutations in RMRP primarily give rise to Cartilage Hair Hypoplasia (CHH), a highly diverse skeletal disorder which can be associated with severe immunodeficiency. Increased availability of RMRP mutation screening has uncovered a number of infants with significant immunodeficiency but only mild or absent skeletal features. We surveyed the clinical and immunological phenotype of children who have undergone allogeneic haematopoietic stem cell transplantation for this condition in the UK.

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.

Perinatal systemic gene delivery using adeno-associated viral vectors.

Neurodegenerative monogenic diseases often affect tissues and organs beyond the nervous system. An effective treatment would require a systemic approach. The intravenous administration of novel therapies is ideal but is hampered by the inability of such drugs to cross the blood-brain barrier (BBB) and precludes efficacy in the central nervous system.

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families.

Targeted gene panel sequencing in children with very early onset inflammatory bowel disease--evaluation and prospective analysis.

Background: Multiple monogenetic conditions with partially overlapping phenotypes can present with inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important.

Design: We have introduced targeted next-generation sequencing (NGS) technology as a prospective screening tool in children with very early onset IBD (VEOIBD).

Identification and validation of loss of function variants in clinical contexts.

The choice of an appropriate variant calling pipeline for exome sequencing data is becoming increasingly more important in translational medicine projects and clinical contexts. Within GOSgene, which facilitates genetic analysis as part of a joint effort of the University College London and the Great Ormond Street Hospital, we aimed to optimize a variant calling pipeline suitable for our clinical context. We implemented the GATK/Queue framework and evaluated the performance of its two callers: the classical UnifiedGenotyper and the new variant discovery tool HaplotypeCaller.