Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.
Hereditary spastic paraplegias and related genetically heterogeneous disorders may be difficult to distinguish clinically. The FA2H gene has been associated with autosomal recessive neurodegenerative phenotypes encompassing spastic paraplegia with or without dystonia, and demyelinating leukodystrophy. To date, few individuals with mutations in the FA2H gene have been described. We report a 5-year-old girl of mixed Filipino and Vietnamese origin who presented with progressive lower limb spasticity and periventricular leukomalacia. The clinical diagnosis of FA2H-associated neurodegeneration was confirmed on the basis of 2 novel mutations in compound heterozygosity in the FA2H gene (p.S70L/p.P323L). This family highlights that FA2H-associated disorders may be underrecognized in children with neurodegeneration of many different ethnicities. Magnetic resonance imaging features play an important role as diagnostic clues in this and other hereditary spastic paraplegias. The consideration of this diagnosis is essential in providing families with important information on prognosis, as well as accurate genetic counseling.
Introduction: The Royal College of Physicians and Surgeons of Canada and the American Accreditation Council for Graduate Medical Education require resident skills in Evidence-Based Medicine and participation in research activities. Our first-year pediatric residents (PGY1s) were required to attend a novel, call-protected, 4-week Academic Skills and Knowledge (ASK) rotation to improve their skills as consumers of medical literature. Objectives of the study were to describe this curriculum and summarize its mixed-methods evaluation. Methods: After 14 months of curriculum development, three annual cohorts of PGY1s wrote identical pre- and post-ASK quizzes (2017-19). In 2018 and 2019, we assessed knowledge retention with PGY1s re-writing the quiz after 6 months. Mean test scores were compared using paired t-tests. In 2017, pre- and post-ASK focus groups assessed resident feelings about the rotation. Results: All eligible PGY1s (n=32) participated. Mean exam scores demonstrated increased knowledge (time0 mean plus/minus SD 52.6 plus/minus 11.0%; vs. time1 80.2 plus/minus 9.0%, p <0.001). Knowledge retention at 6 months was intermediate (time2 70.2 plus/minus12.0%; time0 vs time2 p<0.001). In the pre-rotation focus group, residents looked forward to ASK; goals centered around growing from learner to expert. Post-ASK, residents were very satisfied. Resident participation in our annual Research Institute poster competition increased linearly from 0% in 2014 to 8% in 2020 (r=0.74, p=0.01). Discussion: The ASK curriculum was successfully implemented, and increased knowledge persisted over time. Residents were satisfied with ASK and appreciated the structured curriculum building on core knowledge that they could immediately apply to their clinical work.
IntroductionMutations in the family of SCN genes encoding sodium channels are responsible for several disorders affecting the central and peripheral nervous systems and muscle. Disease arising from sodium channel mutants range from the relatively benign (e.g. mild myotonia) to the fatal (e.g. long-QT syndrome), with a wide variety of disorders spanning the spectrum of severity. Identified SCN4a mutations to date have been consistently autosomal dominant and associated with paramyotonia congenita, potassium-mediated periodic paralysis or aggravated myotonia due to defects altering the biophysical properties of sodium channels that mediate membrane hyper- or hypo-excitability. Here we describe a newly recognised autosomal-recessive syndrome comprising severe congenital hypotonia with respiratory failure in a family of Punjabi descent, with 2 of 3 children affected.Methods and resultsUsing whole exome sequencing we identified two new mutations (g. 62025363 C >T, D1069N and g. 62025425 T >G, splice site) in the SCN4A gene, confirmed via Sanger sequencing. Reverse transcriptase polymerase chain reaction shows that the splice-site mutation in SCN4A leads to altered RNA. To investigate the impact of the missense mutation, c.3205G >A, Chinese hamster ovary (CHOk1) cells transfected with either a WT or D1069N SCN4A were examined for their biophysical properties. A set of depolarizing test pulses was used to measure the voltage dependence of activation and indicated biophysical changes in the encoded voltage-gated sodium channel (NaV1.4).ConclusionsTogether, our findings characterise the first reported evidence of an autosomal recessive SCN4a sodium channelopathy comprising severe congenital neuromuscular hypotonia and respiratory failure with biophysical dysfunction of NaV1.4 attributable to SCN4a compound heterozygous gene mutation.
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