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Optimizing the diagnosis of neuromuscular disorders (NMDs) requires an iterative clinical/genomic approach. Despite advanced genomic sequencing technologies, it is estimated that about half of the patients do not receive a confirmed molecular diagnosis after initial genetic work-up. Here we evaluated 66 index patients with pediatric neuromuscular disorders of unknown genetic etiology recruited from a tertiary neuromuscular center in Turkey, in whom initial exome sequencing (ES) had been unrevealing. Diagnostic algorithm included singleton, trio or quartet research-based ES followed by clinical phenotype reassessment-driven prioritization of data analysis and the addition of bioinformatic pipelines that include copy number variants and short tandem repeat analysis followed by genome sequencing (GS), RNA sequencing and/or target gene sequencing. At data cut-off, ES sequencing for 42/66 of the cohort was completed including repeat ES for all, in combination with GS (n= 5) and RNAseq (n= 4). Interim diagnostic yield was 31/42 (73.8%) which included ES and CNV analysis (n= 1); ES and direct gene sequencing (n= 1); ES and mitochondrial filter (n= 1); ES and SMA Finder (n= 1); GS and gene sequencing (n= 1); GS and RNAseq (n= 1); GS, RNAseq and CNV analysis (n= 3) were diagnostic pathways. Several candidates, including novel candidate genes for the undiagnosed group, are in further analysis (n= 11). The initial analysis of our highly selected cohort highlights the value of an iterative phenotype driven approach to research-based sequencing data analyses with the integration of additional bioinformatics approaches to improve the genetic diagnostic yield. [ABSTRACT FROM AUTHOR]

Genome sequencing adds an important diagnostic tool for patients with unsolved or atypical phenotypes. Here we describe the diagnostic journey in a patient with an atypical progressive course of riboflavin and thiamine responsive neurodegeneration, who is finally diagnosed with SMA through genome sequencing. The patient is a 28-year-old female presenting at age 4 years with fever, nausea, vomiting and leg pain, followed by itchy lesions on the soles of the feet, burning pain, frequent falls, and foot drop. At age 6-7 years, she developed progressive lower and then upper extremity weakness with loss of independent ambulation at age 10 years. She had scoliosis surgery at age 14 years and developed sudden respiratory failure requiring full-time ventilation via tracheostomy at age 19 years. She had progressive tongue and facial fasciculations with a dramatic response to high dose riboflavin and thiamine supplementation. Family history was significant for an undiagnosed older brother who passed away at age 7 years, who presented with a fever episode at age 2 years followed by progressive difficulty in walking and steppage gait. EMG and muscle biopsy revealed chronic neurogenic changes. Testing for SMN (RT-PCR) was negative. Repeat-SMN testing (MLPA) revealed heterozygous carrier status for the common SMN exon 7 deletion. Three independent WES studies were unrevealing. Research-based genome sequencing with an SMA centric re-analysis tool identified a novel missense variant c.809G>T p.(Ser270Ile) in SMN1, which was previously not recognized as located in SMN1. While exome sequencing did not allow the position of this variant to be unambiguously resolved between SMN1 and SMN2, genome sequencing did unambiguously position the variant on SMN1 via phasing with intronic sequence differences between SMN1 & SMN2. SMN2 copy number was 1. The parental data enabled a determination of compound heterozygosity. Location of intragenic mutations in SMN1 are expected to contribute to clinical severity. In the era of diseases modifying treatments, WGS, followed by direct gene sequencing, ended this diagnostic odyssey lasting more than two decades. [ABSTRACT FROM AUTHOR]

Objective: To present the functional status of a child with 16p13.11 microduplication syndrome by evaluating it under the International Classification of the World Health Organization's International Framework for Functioning, Disability and Health (ICF). Case Description: An 11-year-old girl with 16p13.11 microduplication syndrome was assessed using the tools classified according to ICF for Children and Youth (ICF-CY) categories to evaluate body function, activity participation, and environmental factors.There was a wide range of problems, from body functions to activity participation and environmental factors. Besides these problems, there were social and cognitive disorders as well. Conclusion: Physical and cognitive problems in body function and activity together constitute great barriers to participation in daily life.

ABSTRACT Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and 1H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls ( P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]