Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.

Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.

Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.

Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation.

Introduction: Presenilin-1 (PSEN1) gene mutations are the most common cause of familial Alzheimer's disease (fAD) and are known to interfere with activity of the membrane imbedded γ-secretase complex. PSEN1 mutations have been shown to shift Amyloid-β precursor protein (AβPP) processing toward amyloid-β (Aβ) 1-42 production. However, less is known about whether PSEN1 mutations may alter the activity of enzymes such as ADAM10, involved with non-amyloidogenic AβPP processing, and markers of oxidative stress.

Lysinuric protein intolerance mimicking -acetylglutamate synthase deficiency in a nine-year-old boy.

We report a 9-year-old boy with lysinuric protein intolerance (LPI). He had developmental delay, short stature, failure to thrive, high-protein food aversion, hypothyroidism, growth hormone deficiency, features of hemophagocytic lymphohistiocytosis (HLH), decreased bone mineral density and multiple thoracic spine compression fractures on X-ray. LPI was suspected, but urine amino acid profile and normal orotic acid did not suggest biochemical diagnosis of LPI.

Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified.

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population.

Purpose: Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia.

Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH.

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS.