Publications by authors named "Sandra Yang"

16 Publications

  • Page 1 of 1

Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders.

Brain 2020 12;143(12):3564-3573

Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, UMR S 1127, Inserm U1127, CNRS UMR 7225, F-75013 Paris, France.

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.
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http://dx.doi.org/10.1093/brain/awaa346DOI Listing
December 2020

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

Authors:
Laura Castilla-Vallmanya Kaja K Selmer Clémantine Dimartino Raquel Rabionet Bernardo Blanco-Sánchez Sandra Yang Margot R F Reijnders Antonie J van Essen Myriam Oufadem Magnus D Vigeland Barbro Stadheim Gunnar Houge Helen Cox Helen Kingston Jill Clayton-Smith Jeffrey W Innis Maria Iascone Anna Cereda Sara Gabbiadini Wendy K Chung Victoria Sanders Joel Charrow Emily Bryant John Millichap Antonio Vitobello Christel Thauvin Frederic Tran Mau-Them Laurence Faivre Gaetan Lesca Audrey Labalme Christelle Rougeot Nicolas Chatron Damien Sanlaville Katherine M Christensen Amelia Kirby Raymond Lewandowski Rachel Gannaway Maha Aly Anna Lehman Lorne Clarke Luitgard Graul-Neumann Christiane Zweier Davor Lessel Bernarda Lozic Ingvild Aukrust Ryan Peretz Robert Stratton Thomas Smol Anne Dieux-Coëslier Joanna Meira Elizabeth Wohler Nara Sobreira Erin M Beaver Jennifer Heeley Lauren C Briere Frances A High David A Sweetser Melissa A Walker Catherine E Keegan Parul Jayakar Marwan Shinawi Wilhelmina S Kerstjens-Frederikse Dawn L Earl Victoria M Siu Emma Reesor Tony Yao Robert A Hegele Olena M Vaske Shannon Rego Kevin A Shapiro Brian Wong Michael J Gambello Marie McDonald Danielle Karlowicz Roberto Colombo Alessandro Serretti Lynn Pais Anne O'Donnell-Luria Alison Wray Simon Sadedin Belinda Chong Tiong Y Tan John Christodoulou Susan M White Anne Slavotinek Deborah Barbouth Dayna Morel Swols Mélanie Parisot Christine Bole-Feysot Patrick Nitschké Véronique Pingault Arnold Munnich Megan T Cho Valérie Cormier-Daire Susanna Balcells Stanislas Lyonnet Daniel Grinberg Jeanne Amiel Roser Urreizti Christopher T Gordon

Genet Med 2020 07 7;22(7):1215-1226. Epub 2020 May 7.

Laboratory of embryology and genetics of human malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

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. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

Results: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

Conclusion: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
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http://dx.doi.org/10.1038/s41436-020-0792-7DOI Listing
July 2020

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

Brain 2020 01;143(1):55-68

Laboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
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http://dx.doi.org/10.1093/brain/awz379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962909PMC
January 2020

Prospective, phenotype-driven selection of critically ill neonates for rapid exome sequencing is associated with high diagnostic yield.

Genet Med 2020 04 29;22(4):736-744. Epub 2019 Nov 29.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

Purpose: To investigate the impact of rapid-turnaround exome sequencing in critically ill neonates using phenotype-based subject selection criteria.

Methods: Intensive care unit babies aged <6 months with hypotonia, seizures, a complex metabolic phenotype, and/or multiple congenital malformations were prospectively enrolled for rapid (<7 day) trio-based exome sequencing. Genomic variants relevant to the presenting phenotype were returned to the medical team.

Results: A genetic diagnosis was attained in 29 of 50 (58%) sequenced cases. Twenty-seven (54%) patients received a molecular diagnosis involving known disease genes; two additional cases (4%) were solved with pathogenic variants found in novel disease genes. In 24 of the solved cases, diagnosis had impact on patient management and/or family members. Management changes included shift to palliative care, medication changes, involvement of additional specialties, and the consideration of new experimental therapies.

Conclusion: Phenotype-based patient selection is effective at identifying critically ill neonates with a high likelihood of receiving a molecular diagnosis via rapid-turnaround exome sequencing, leading to faster and more accurate diagnoses, reducing unnecessary testing and procedures, and informing medical care.
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http://dx.doi.org/10.1038/s41436-019-0708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127968PMC
April 2020

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.

Genet Med 2020 03 14;22(3):538-546. Epub 2019 Nov 14.

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
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http://dx.doi.org/10.1038/s41436-019-0693-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060121PMC
March 2020

The skeletal phenotype of intermediate GM1 gangliosidosis: Clinical, radiographic and densitometric features, and implications for clinical monitoring and intervention.

Bone 2020 02 6;131:115142. Epub 2019 Nov 6.

Department of Genetics and Metabolism, Rare Disease Institute, Children's National Medical Center, Washington, DC, United States of America. Electronic address:

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1 encoding a lysosomal β-galactosidase. This disease is a continuum from the severe infantile form with rapid neurological decline to the chronic adult form, which is not life-limiting. The intermediate or type 2 form can be further classified into late infantile and juvenile forms. The frequency and severity of skeletal outcomes in late infantile and juvenile patients have not been characterized. Our goals are to describe the radiological skeletal abnormalities, bone mineral density (BMD), and frequency of fractures in patients with intermediate GM1 gangliosidosis. We evaluated 13 late infantile and 21 juvenile patients as part of an ongoing natural history study. Average time from onset of symptoms to diagnosis was 1.9 and 6.3 years for late infantile and juvenile patients, respectively. All late infantile patients had odontoid hypoplasia and pear-shaped vertebral bodies, the frequency of which was significantly different than in patients with juvenile disease (none and 14%, respectively). Juvenile patients had irregular endplates of the vertebral bodies (15/21), central indentation of endplates (10/21), and squared and flat vertebral bodies (10/21); all allowed radiographic differentiation from late infantile patients. Lumbar spine, femoral neck, and total hip BMD were significantly decreased (-2.1, -2.2, and -1.8 Z-scores respectively). Lumbar spine BMD peaked at 19 years, while distal forearm BMD peaked at 30 years. Despite low BMD, no patients exhibited fractures. We have demonstrated that all late infantile patients have some degree of odontoid hypoplasia suggesting the need for cervical spine evaluation particularly prior to anesthesia, whereas juvenile patients had variable skeletal involvement often affecting activities of daily living. Type 2 GM1 gangliosidosis patients have skeletal abnormalities that are both an early indication of their diagnosis, and require monitoring and management to ensure the highest possible quality of life.
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http://dx.doi.org/10.1016/j.bone.2019.115142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937522PMC
February 2020

Clinical utility of exome sequencing in infantile heart failure.

Genet Med 2020 02 17;22(2):423-426. Epub 2019 Sep 17.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Pediatric cardiomyopathy is rare, has a broad differential diagnosis, results in high morbidity and mortality, and has suboptimal diagnostic yield using next-generation sequencing panels. Exome sequencing has reported diagnostic yields ranging from 30% to 57% for neonates in intensive care units. We aimed to characterize the clinical utility of exome sequencing in infantile heart failure.

Methods: Infants diagnosed with acute heart failure prior to 1 year old over a period of 34 months at a large tertiary children's hospital were recruited. Demographic and diagnostic information was obtained from medical records. Fifteen eligible patients were enrolled.

Results: Dilated cardiomyopathy was the predominant cardiac diagnosis, seen in 60% of patients. A molecular diagnosis was identified in 66.7% of patients (10/15). Of those diagnoses, 70% would not have been detected using multigene next-generation sequencing panels focused on cardiomyopathy or arrhythmia disease genes. Genetic testing changed medical decision-making in 53% of all cases and 80% of positive cases, and was especially beneficial when testing was expedited.

Conclusion: Given the broad differential diagnosis and critical status of infants with heart failure, rapid exome sequencing provides timely diagnoses, changes medical management, and should be the first-tier molecular test.
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http://dx.doi.org/10.1038/s41436-019-0654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339672PMC
February 2020

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

Brain 2019 09;142(9):2617-2630

Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
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http://dx.doi.org/10.1093/brain/awz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736092PMC
September 2019

MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis.

Am J Med Genet A 2016 Mar 8;170(3):634-44. Epub 2015 Dec 8.

Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N-acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally-invasive outcome measures for clinical trials.
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http://dx.doi.org/10.1002/ajmg.a.37468DOI Listing
March 2016

Racial and ethnic disparities in health care-associated Clostridium difficile infections in the United States: State of the science.

Am J Infect Control 2016 Jan 9;44(1):91-6. Epub 2015 Oct 9.

Office of Disease Prevention and Health Promotion, US Department of Health and Human Services, Rockville, MD.

Background: Among health care-associated infections (HAIs), Clostridium difficile infections (CDIs) are a major cause of morbidity and mortality in the United States. As national progress toward CDI prevention continues, it will be critical to ensure that the benefits from CDI prevention are realized across different patient demographic groups, including any targeted interventions.

Methods: Through a comprehensive review of existing evidence for racial/ethnic and other disparities in CDIs, we identified a few general trends, but the results were heterogeneous and highlight significant gaps in the literature.

Results: The majority of analyzed studies identified white patients as at increased risk of CDIs, although there is a very limited literature base, and many studies had significant methodological limitations.

Conclusion: Key recommendations for future research are provided to address antimicrobial stewardship programs and populations that may be at increased risk for CDIs.
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http://dx.doi.org/10.1016/j.ajic.2015.08.007DOI Listing
January 2016

Adverse Drug Event Prevention: 2014 Action Plan Conference.

Am J Med Qual 2016 09 29;31(5):476-85. Epub 2015 May 29.

US Department of Health and Human Services, Office of Disease Prevention and Health Promotion, Rockville, MD

Adverse drug events (ADEs) have been highlighted as a national patient safety and public health challenge by the National Action Plan for Adverse Drug Event Prevention (ADE Action Plan), which was released by the Office of Disease Prevention and Health Promotion in August 2014. The following October, the ADE Prevention: 2014 Action Plan Conference provided an opportunity for federal agencies, national experts, and stakeholders to coordinate and collaborate in the initiative to reduce preventable ADEs. The single-day conference included morning plenary sessions focused on the surveillance, evidence-based prevention, incentives and oversights, and additional research needs of the drug classes highlighted in the ADE Action Plan: anticoagulants, diabetes agents, and opioids. Afternoon breakout sessions allowed for facilitated discussions on measures for tracking national progress in ADE prevention and the identification of opportunities to ensure safe and high-quality health care and medication use.
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http://dx.doi.org/10.1177/1062860615588105DOI Listing
September 2016

A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings.

J Hum Genet 2015 Jul 26;60(7):363-9. Epub 2015 Mar 26.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.
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http://dx.doi.org/10.1038/jhg.2015.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537600PMC
July 2015

Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies.

Mol Genet Metab Rep 2014 11;1:66-70. Epub 2014 Feb 11.

Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.
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http://dx.doi.org/10.1016/j.ymgmr.2013.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121315PMC
February 2014

Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis.

Neurology 2012 Jul 6;79(2):123-6. Epub 2012 Jun 6.

NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research, Neurogenetics Branch, Bethesda, MD, USA.

Objective: To utilize high-throughput sequencing to determine the etiology of juvenile-onset neurodegeneration in a 19-year-old woman with progressive motor and cognitive decline.

Methods: Exome sequencing identified an initial list of 133,555 variants in the proband's family, which were filtered using segregation analysis, presence in dbSNP, and an empirically derived gene exclusion list. The filtered list comprised 52 genes: 21 homozygous variants and 31 compound heterozygous variants. These variants were subsequently scrutinized with predicted pathogenicity programs and for association with appropriate clinical syndromes.

Results: Exome sequencing data identified 2 GLB1 variants (c.602G>A, p.R201H; c.785G>T, p.G262V). β-Galactosidase enzyme analysis prior to our evaluation was reported as normal; however, subsequent testing was consistent with juvenile-onset GM1-gangliosidosis. Urine oligosaccharide analysis was positive for multiple oligosaccharides with terminal galactose residues.

Conclusions: We describe a patient with juvenile-onset neurodegeneration that had eluded diagnosis for over a decade. GM1-gangliosidosis had previously been excluded from consideration, but was subsequently identified as the correct diagnosis using exome sequencing. Exome sequencing can evaluate genes not previously associated with neurodegeneration, as well as most known neurodegeneration-associated genes. Our results demonstrate the utility of "agnostic" exome sequencing to evaluate patients with undiagnosed disorders, without prejudice from prior testing results.
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http://dx.doi.org/10.1212/WNL.0b013e31825f047aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390543PMC
July 2012

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.

Genet Med 2012 Jan 26;14(1):51-9. Epub 2011 Sep 26.

NIH Undiagnosed Diseases Program, NIH, Bethesda, Maryland, USA.

Purpose: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years.

Methods: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.

Results: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.

Conclusion: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.
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http://dx.doi.org/10.1038/gim.0b013e318232a005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098846PMC
January 2012

Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis.

Mol Genet Metab 2009 Aug 3;97(4):284-91. Epub 2009 May 3.

Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ont., Canada.

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal beta-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification.
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http://dx.doi.org/10.1016/j.ymgme.2009.04.013DOI Listing
August 2009