Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.

Background: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP ) receptor type 1 (IP R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3.

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms.

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

Purpose: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

Methods: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers.

Reducing emergency hospital admissions: a population health complex intervention of an enhanced model of primary care and compassionate communities.

Background: Reducing emergency admissions to hospital has been a cornerstone of healthcare policy. Little evidence exists to show that systematic interventions across a population have achieved this aim. The authors report the impact of a complex intervention over a 44-month period in Frome, Somerset, on unplanned admissions to hospital.

Further Clinical Delineation of the MEF2C Haploinsufficiency Syndrome: Report on New Cases and Literature Review of Severe Neurodevelopmental Disorders Presenting with Seizures, Absent Speech, and Involuntary Movements.

Mutations in the ( ) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement.

ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.

Calcium (Ca ) is a physiological key factor, and the precise modulation of free cytosolic Ca levels regulates multiple cellular functions. Store-operated Ca entry (SOCE) is a major mechanism controlling Ca homeostasis, and is mediated by the concerted activity of the Ca sensor STIM1 and the Ca channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency.

Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism.

Community engagement and education: addressing the needs of South Asian families with genetic disorders.

Consanguineous marriage is common among the South Asian heritage community in the UK. While conferring social and cultural benefits, consanguinity is associated with an increased risk of autosomal recessive disorders and an increase in childhood death and disability. We have previously developed a genetic service to address the needs of this community.

Responding to the increased genetic risk associated with customary consanguineous marriage among minority ethnic populations: lessons from local innovations in England.

Populations practising customary consanguineous marriage have a higher incidence of autosomal recessive genetic disorders than those in which reproductive partners are usually unrelated. In the absence of any national-level response, English service developments to address the additional needs of families living with or at risk of such disorders have been locally led. These interventions remain in their infancy here, as elsewhere in Europe, and important questions remain regarding how appropriate, effective and sustainable responses can be operationalised in practice.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

Objectives: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis.

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these.

Heterogeneity in spinal muscular atrophy with respiratory distress type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically heterogeneous disorder linked to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. Most infants with SMARD1 present between six weeks and six months of age with respiratory distress secondary to diaphragmatic weakness and progressive distal weakness. Sensory and autonomic dysfunctions sometimes accompany the motor weakness.

Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease.

Perrault syndrome is a genetically and clinically heterogeneous autosomal-recessive condition characterized by sensorineural hearing loss and ovarian failure. By a combination of linkage analysis, homozygosity mapping, and exome sequencing in three families, we identified mutations in CLPP as the likely cause of this phenotype. In each family, affected individuals were homozygous for a different pathogenic CLPP allele: c.

Trouble with ataxia: A longitudinal qualitative study of the diagnosis and medical management of a group of rare, progressive neurological conditions.

Objectives: An exploratory investigation of diagnosis and management in progressive ataxias: rare neurological conditions usually affecting balance, mobility and speech.

Methods: A longitudinal qualitative study into the experiences of people with ataxia and neurologists. Thematic analysis and follow-up interviews were used to determine diagnosis and management issues over time.

'You don't get told anything, they don't do anything and nothing changes'. Medicine as a resource and constraint in progressive ataxia.

Background: Progressive ataxias are neurological disorders affecting balance, co-ordination of movement and speech.

Objective: A qualitative study was undertaken to discover patients' experiences of ataxia and its symptoms.

Participants: Thirty-eight people with ataxia recruited from patient support groups and two hospital outpatients departments.