A Novel Frameshift Mutation, [p.Asp896ArgfsX79], Leading to Malignant Ventricular Arrhythmia, Identified After Treatment of Gastrointestinal Bleeding.

A novel frameshift mutation in the gene for long QT syndrome type 2 (LQTS2) was identified after torsades des pointes ventricular tachycardia in a 49-year-old patient managed with octreotide and nadolol for an acute variceal bleed. In spite of removal of offending medications, and correction of underlying electrolyte abnormalities, the patient's QT interval remained prolonged-at 521 ms-raising the suspicion of an underlying channelopathy. Genetic studies confirmed heterozygosity for a novel frameshift mutation for the gene, D896Rfs X79.

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.

Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor as the cause of microcephaly-micromelia syndrome.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS).

A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome.

We present an 18-year-old boy with cerebral palsy, intellectual disability, speech delay, and seizures. He carries a likely pathogenic 1.3 Mb de novo heterozygous deletion in the 4q21.

A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population.

Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease.

The differential diagnosis of spastic diplegia.

Spastic diplegia is the most common form of cerebral palsy worldwide. Many disorders mimic spastic diplegia, which can result in misdiagnosis for the child with resultant negative treatment and family counselling implications. In this paper, the authors provide a brief review of spastic diplegia and the various disorders in the differential diagnosis.

Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.

Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements.

Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome.

Perinatal and childhood morbidity and mortality in congenital analbuminemia.

Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact.

Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series.

Introduction: Congenital central hypoventilation syndrome is an autosomal dominant disorder that classically presents as sudden death in infancy secondary to central hypoventilation. Most cases are caused by polyalanine repeat mutations in the paired-like homeobox 2B gene, PHOX2B. More severe disease is typically associated with nonpolyalanine repeat mutations.

GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome.

Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss.

Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ¹-pyrroline-5-carboxylate synthase (P5CS).

We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ¹-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason.

Familial interstitial pulmonary fibrosis: a large family with atypical clinical features.

A large kindred of familial pulmonary fibrosis is reported. Six members from the first two generations of this particular kindred were described more than 40 years previously; six more individuals from the third and fourth generations have also been evaluated. The proband, now 23 years of age, has mild disease; the other 11 documented affected family members all died from their disease at an average age of 37 years (range 25 to 50 years).

Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.

Context: Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation.

Objective: To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients.

Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.

To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs.

Sotos syndrome: antenatal presentation.

There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements.

Clinical and radiologic findings in an adult male with dysosteosclerosis.

Dysosteosclerosis is a rare autosomal recessive skeletal dysplasia characterized by osteosclerosis and platyspondyly. A case of dysosteosclerosis in a 17-year-old male from our institution was first published by Houston et al. 1978.

Congenital anterolateral tibial bowing and polydactyly: a case report.

Congenital anterolateral bowing of the tibia is a rare deformity that may lead to pseudarthrosis and risk of fracture. This is commonly associated with neurofibromatosis type 1. In this report, we describe a 15-month old male with congenital anterolateral bowing of the right tibia and associated hallux duplication.

Ophthalmic findings in Setleis syndrome: two new cases in a mother and son.

Case Report: Setleis syndrome is a rare ectodermal dysplasia with characteristic ophthalmic findings. We describe the first 2 reported cases in Canadian individuals of Aboriginal descent.

Comments: Although most ophthalmic findings are benign, it is important to recognize the clinical significance for management and genetic counselling.

Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation.

Background: Women with a BRCA1 or BRCA2 genetic mutation have several options for cancer prevention, including prophylactic surgery, chemoprevention and screening. In this study we report on preventive practices used by women with and without breast cancer and examine differences in their selection of preventive practices according to geographic area in Canada.

Methods: Canadian women with a BRCA1 or BRCA2 mutation were followed after genetic testing and questioned about their preventive practices.