Publications by authors named "Ryan J Taft"

90 Publications

Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy.

Pediatr Neurol 2021 Aug 14;121:11-19. Epub 2021 May 14.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study.

Methods: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case.

Results: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia.

Conclusions: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.04.014DOI Listing
August 2021

Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2).

Am J Med Genet A 2021 Jul 1;185(7):2190-2197. Epub 2021 May 1.

Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.
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http://dx.doi.org/10.1002/ajmg.a.62219DOI Listing
July 2021

Fatal perinatal mitochondrial cardiac failure caused by recurrent duplications in the locus.

Med (N Y) 2021 Jan 9;2(1):49-73. Epub 2020 Jul 9.

Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.

Background: In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively.

Methods: Whole exome, whole genome and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease.

Findings: We report six different duplications in the gene locus causing a distinctive presentation including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. The recurrent 68 Kb duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue.

Conclusions: duplications appear to act in a dominant-negative manner and the inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience the locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease but the repetitive nature of the locus means diagnoses may be frequently missed by current genomic strategies.

Funding: Australian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.
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http://dx.doi.org/10.1016/j.medj.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875323PMC
January 2021

Cyrius: accurate CYP2D6 genotyping using whole-genome sequencing data.

Pharmacogenomics J 2021 Apr 18;21(2):251-261. Epub 2021 Jan 18.

Illumina Inc., 5200 Illumina Way, San Diego, CA, USA.

Responsible for the metabolism of ~21% of clinically used drugs, CYP2D6 is a critical component of personalized medicine initiatives. Genotyping CYP2D6 is challenging due to sequence similarity with its pseudogene paralog CYP2D7 and a high number and variety of common structural variants (SVs). Here we describe a novel bioinformatics method, Cyrius, that accurately genotypes CYP2D6 using whole-genome sequencing (WGS) data. We show that Cyrius has superior performance (96.5% concordance with truth genotypes) compared to existing methods (84-86.8%). After implementing the improvements identified from the comparison against the truth data, Cyrius's accuracy has since been improved to 99.3%. Using Cyrius, we built a haplotype frequency database from 2504 ethnically diverse samples and estimate that SV-containing star alleles are more frequent than previously reported. Cyrius will be an important tool to incorporate pharmacogenomics in WGS-based precision medicine initiatives.
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http://dx.doi.org/10.1038/s41397-020-00205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997805PMC
April 2021

Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease.

NPJ Genom Med 2020 23;5:47. Epub 2020 Oct 23.

Broad Institute of MIT and Harvard, Cambridge, MA USA.

Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders; however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading healthcare and research organizations in the US and Canada, was formed to expand access to high-quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders, and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice, and support safe and effective WGS testing for diagnosis of germline disease.
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http://dx.doi.org/10.1038/s41525-020-00154-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585436PMC
October 2020

Phenotypic and Imaging Spectrum Associated With WDR45.

Pediatr Neurol 2020 08 11;109:56-62. Epub 2020 Mar 11.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.

Methods: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected.

Results: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.

Conclusions: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387198PMC
August 2020

De novo mutations in TOMM70, a receptor of the mitochondrial import translocase, cause neurological impairment.

Hum Mol Genet 2020 06;29(9):1568-1579

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

The translocase of outer mitochondrial membrane (TOMM) complex is the entry gate for virtually all mitochondrial proteins and is essential to build the mitochondrial proteome. TOMM70 is a receptor that assists mainly in mitochondrial protein import. Here, we report two individuals with de novo variants in the C-terminal region of TOMM70. While both individuals exhibited shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset. Both individuals were undiagnosed despite extensive genetics workups. Individual 1 was found to have a p.Thr607Ile variant while Individual 2 was found to have a p.Ile554Phe variant in TOMM70. To functionally assess both TOMM70 variants, we replaced the Drosophila Tom70 coding region with a Kozak-mini-GAL4 transgene using CRISPR-Cas9. Homozygous mutant animals die as pupae, but lethality is rescued by the mini-GAL4-driven expression of human UAS-TOMM70 cDNA. Both modeled variants lead to significantly less rescue indicating that they are loss-of-function alleles. Similarly, RNAi-mediated knockdown of Tom70 in the developing eye causes roughening and synaptic transmission defect, common findings in neurodegenerative and mitochondrial disorders. These phenotypes were rescued by the reference, but not the variants, of TOMM70. Altogether, our data indicate that de novo loss-of-function variants in TOMM70 result in variable white matter disease and neurological phenotypes in affected individuals.
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http://dx.doi.org/10.1093/hmg/ddaa081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268787PMC
June 2020

ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data.

Genome Biol 2020 04 28;21(1):102. Epub 2020 Apr 28.

Illumina Inc., 5200 Illumina Way, San Diego, CA, 92122, USA.

Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
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http://dx.doi.org/10.1186/s13059-020-02017-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187524PMC
April 2020

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.

Ann Neurol 2020 08 9;88(2):264-273. Epub 2020 Jun 9.

Illumina, San Diego, California, USA.

Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.

Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS.

Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study.

Interpretation: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.
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http://dx.doi.org/10.1002/ana.25757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061316PMC
August 2020

Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.

Genet Med 2020 05 18;22(5):945-953. Epub 2020 Feb 18.

Illumina Inc., San Diego, CA, USA.

Purpose: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics.

Methods: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.

Results: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers.

Conclusion: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.
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http://dx.doi.org/10.1038/s41436-020-0754-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200598PMC
May 2020

Genome sequencing in persistently unsolved white matter disorders.

Ann Clin Transl Neurol 2020 01 7;7(1):144-152. Epub 2020 Jan 7.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.
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http://dx.doi.org/10.1002/acn3.50957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952322PMC
January 2020

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.

Am J Hum Genet 2019 11 3;105(5):996-1004. Epub 2019 Oct 3.

Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands. Electronic address:

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848986PMC
November 2019

ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions.

Bioinformatics 2019 11;35(22):4754-4756

Illumina Inc., San Diego, CA 92122, USA.

Summary: We describe a novel computational method for genotyping repeats using sequence graphs. This method addresses the long-standing need to accurately genotype medically important loci containing repeats adjacent to other variants or imperfect DNA repeats such as polyalanine repeats. Here we introduce a new version of our repeat genotyping software, ExpansionHunter, that uses this method to perform targeted genotyping of a broad class of such loci.

Availability And Implementation: ExpansionHunter is implemented in C++ and is available under the Apache License Version 2.0. The source code, documentation, and Linux/macOS binaries are available at https://github.com/Illumina/ExpansionHunter/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853681PMC
November 2019

Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases.

J Med Genet 2019 12 25;56(12):783-791. Epub 2019 Apr 25.

Illumina Inc, San Diego, California, USA.

Up to 350 million people worldwide suffer from a rare disease, and while the individual diseases are rare, in aggregate they represent a substantial challenge to global health systems. The majority of rare disorders are genetic in origin, with children under the age of five disproportionately affected. As these conditions are difficult to identify clinically, genetic and genomic testing have become the backbone of diagnostic testing in this population. In the last 10 years, next-generation sequencing technologies have enabled testing of multiple disease genes simultaneously, ranging from targeted gene panels to exome sequencing (ES) and genome sequencing (GS). GS is quickly becoming a practical first-tier test, as cost decreases and performance improves. A growing number of studies demonstrate that GS can detect an unparalleled range of pathogenic abnormalities in a single laboratory workflow. GS has the potential to deliver unbiased, rapid and accurate molecular diagnoses to patients across diverse clinical indications and complex presentations. In this paper, we discuss clinical indications for testing and historical testing paradigms. Evidence supporting GS as a diagnostic tool is supported by superior genomic coverage, types of pathogenic variants detected, simpler laboratory workflow enabling shorter turnaround times, diagnostic and reanalysis yield, and impact on healthcare.
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http://dx.doi.org/10.1136/jmedgenet-2019-106111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929710PMC
December 2019

Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.

Am J Hum Genet 2019 05 11;104(5):925-935. Epub 2019 Apr 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507048PMC
May 2019

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

NPJ Genom Med 2019 14;4. Epub 2019 Feb 14.

1Illumina, Inc, San Diego, CA 92122 USA.

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% ( = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% ( = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% ( = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
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http://dx.doi.org/10.1038/s41525-018-0076-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375919PMC
February 2019

Correction: Estimating the burden and economic impact of pediatric genetic disease.

Genet Med 2019 Sep;21(9):2161

Illumina, Inc., 5200 Illumina Way, San Diego, CA, USA.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY-NC-ND 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41436-019-0458-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608339PMC
September 2019

Biallelic variants in and cause deafness and (ovario)leukodystrophy.

Neurology 2019 03 8;92(11):e1225-e1237. Epub 2019 Feb 8.

From the Departments of Child Neurology (M.S.v.d.K., M. Breur) and Neuropathology (M. Bugiani, M. Breur), and Metabolic Unit, Department of Clinical Chemistry (M.I.M., D.E.C.S., G.S.S.), Amsterdam University Medical Centers and Amsterdam Neuroscience; Department of Functional Genomics (M.S.v.d.K.), Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands; Genetic Metabolic Disorders Research Unit (L.G.R., J. Christodoulou), The Children's Hospital at Westmead, and Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, NSW, Australia; Architecture et Réactivité de l'ARN (J.R.-T., M.F.), UPR 9002, Université de Strasbourg, CNRS, Strasbourg, France; Institute for Molecular Bioscience (J. Crawford, C.S.), University of Queensland, St. Lucia, Queensland, Australia; Department of Neurology (J.v.G.), Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen; Department of Clinical Genetics (M.S.), Radboud University Medical Center, Nijmegen, the Netherlands; Departement Génétique Médicale (M.W.), Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, France; Department of Clinical Genetics (Q.W.), Amsterdam University Medical Centers, the Netherlands; UF Innovation en Diagnostic Génomique des Maladies Rares (F.T.M.-T.), Centre Hospitalier Universitaire de Dijon, France; Radboud Center for Mitochondrial Medicine (R.J.R.), Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, the Netherlands; Illumina Inc. (R.J.T.), San Diego, CA; AP-HP (B.K., F.M.), La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris; INSERM U 1127 (B.K., C.D., F.M.), CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Murdoch Children's Research Institute (J. Christodoulou, C.S.), Parkville, Victoria, Australia; Department of Paediatrics (J. Christodoulou), University of Melbourne, Australia; Institute of Human Genetics (C.D.), University Hospital Essen, University Duisburg-Essen, Germany; and Sorbonne Universités (F.M.), Neurometabolic Clinical Research Group, Paris, France.

Objective: To describe the leukodystrophy caused by pathogenic variants in and , encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively.

Methods: We composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in or . Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patients' lymphoblasts and fibroblasts.

Results: Patients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with and pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patients' lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity.

Conclusion: This study adds and pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.
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http://dx.doi.org/10.1212/WNL.0000000000007098DOI Listing
March 2019

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

Genet Med 2019 08 25;21(8):1797-1807. Epub 2019 Jan 25.

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.

Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.

Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.

Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.
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http://dx.doi.org/10.1038/s41436-019-0433-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752677PMC
August 2019

Leukoencephalopathy due to variants in associated congenital myasthenic syndrome.

Neurology 2019 02 11;92(6):e587-e593. Epub 2019 Jan 11.

From the Murdoch Children's Research Institute (G.H., C.S.), Parkville, Melbourne; Institute for Molecular Bioscience (G.H., J.C., C.S.), the University of Queensland, Brisbane, Australia; Neurology Division (S.S., B.P., P.J.), Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India; Division of Neurology (P.J.), Department of Pediatrics, the Hospital for Sick Children, Toronto, Canada; Data61 (S.J.B.), Commonwealth Scientific and Industrial Research Organisation, Brisbane, Australia; Hôpital Marin (J.A.U.), Centre Neuromusculaire, Filnemus, Hendaye, France; Department of Pathology (R.K.S.), G.B. Pant Hospital, New Delhi, India; Illumina, Inc. (R.J.T.), San Diego, CA; Department of Child Neurology (M.S.v.d.K.), Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience; and Department of Functional Genomics (M.S.v.d.K.), Neuroscience Campus Amsterdam, the Netherlands.

Objective: To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease.

Methods: Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents.

Results: All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response.

Conclusions: encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in -related disease and suggest that mitochondrial dysfunction could contribute to this disorder.
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http://dx.doi.org/10.1212/WNL.0000000000006886DOI Listing
February 2019

Estimating the burden and economic impact of pediatric genetic disease.

Genet Med 2019 08 20;21(8):1781-1789. Epub 2018 Dec 20.

Illumina, Inc., 5200 Illumina Way, San Diego, 92122, CA, USA.

Purpose: To identify the economic impact of pediatric patients with clinical indications of genetic disease (GD) on the US health-care system.

Methods: Using the 2012 Kids' Inpatient Database, we identified pediatric inpatient discharges with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes linked to genetic disease, including well-established genetic disorders, neurological diseases, birth defects, and other physiological or functional abnormalities with a genetic basis. Cohort characteristics and health-care utilization measures were analyzed. Discharges with a GD-associated primary diagnosis were used to estimate the minimum burden; discharges with GD-associated primary or secondary codes established the maximum burden.

Results: Of 5.85 million weighted discharges, 2.6-14% included GD-associated ICD-9-CM codes. For these discharges, mean total costs were $16,000-77,000 higher (P < 0.0001) in neonates and $12,000-17,000 higher (P < 0.0001) in pediatric patients compared with background, corresponding to significantly higher total charges and lengths of stay. Aggregate total charges for suspected GD accounted for $14 to $57 billion (11-46%) of the "national bill" for pediatric patients in 2012.

Conclusion: Pediatric inpatients with diagnostic codes linked to genetic disease have a significant and disproportionate impact on resources and costs in the US health-care system.
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http://dx.doi.org/10.1038/s41436-018-0398-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752475PMC
August 2019

Microdeletions excluding YWHAE and PAFAH1B1 cause a unique leukoencephalopathy: further delineation of the 17p13.3 microdeletion spectrum.

Genet Med 2019 07 20;21(7):1652-1656. Epub 2018 Dec 20.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Purpose: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci.

Methods: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing.

Results: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype.

Conclusion: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.
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http://dx.doi.org/10.1038/s41436-018-0358-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586530PMC
July 2019

Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.

Mol Genet Metab 2019 01 8;126(1):53-63. Epub 2018 Nov 8.

Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA. Electronic address:

Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.
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http://dx.doi.org/10.1016/j.ymgme.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707637PMC
January 2019

Diverse RNA interference strategies in early-branching metazoans.

BMC Evol Biol 2018 11 1;18(1):160. Epub 2018 Nov 1.

School of Biological Sciences, University of Queensland, Brisbane, QLD, 4072, Australia.

Background: Micro RNAs (miRNAs) and piwi interacting RNAs (piRNAs), along with the more ancient eukaryotic endogenous small interfering RNAs (endo-siRNAs) constitute the principal components of the RNA interference (RNAi) repertoire of most animals. RNAi in non-bilaterians - sponges, ctenophores, placozoans and cnidarians - appears to be more diverse than that of bilaterians, and includes structurally variable miRNAs in sponges, an enormous number of piRNAs in cnidarians and the absence of miRNAs in ctenophores and placozoans.

Results: Here we identify thousands of endo-siRNAs and piRNAs from the sponge Amphimedon queenslandica, the ctenophore Mnemiopsis leidyi and the cnidarian Nematostella vectensis using a computational approach that clusters mapped small RNA sequences and annotates each cluster based on the read length and relative abundance of the constituent reads. This approach was validated on 11 small RNA libraries in Drosophila melanogaster, demonstrating the successful annotation of RNAi-associated loci with properties consistent with previous reports. In the non-bilaterians we uncover seven new miRNAs from Amphimedon and four from Nematostella as well as sub-populations of candidate cis-natural antisense transcript (cis-NAT) endo-siRNAs. We confirmed the absence of miRNAs in Mnemiopsis but detected an abundance of endo-siRNAs in this ctenophore. Analysis of putative piRNA structure suggests that conserved localised secondary structures in primary transcripts may be important for the production of mature piRNAs in Amphimedon and Nematostella, as is also the case for endo-siRNAs.

Conclusion: Together, these findings suggest that the last common ancestor of extant animals did not have the entrained RNAi system that typifies bilaterians. Instead it appears that bilaterians, cnidarians, ctenophores and sponges express unique repertoires and combinations of miRNAs, piRNAs and endo-siRNAs.
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http://dx.doi.org/10.1186/s12862-018-1274-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211395PMC
November 2018

Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.

Genet Med 2019 05 8;21(5):1121-1130. Epub 2018 Oct 8.

Illumina Inc., San Diego, CA, USA.

Purpose: Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test.

Methods: We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.

Results: We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs.

Conclusion: Robust identification of CNVs by GS is possible within a clinical testing environment.
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http://dx.doi.org/10.1038/s41436-018-0295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752263PMC
May 2019

Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy.

Am J Hum Genet 2018 10 27;103(4):602-611. Epub 2018 Sep 27.

Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada. Electronic address:

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36 variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.
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http://dx.doi.org/10.1016/j.ajhg.2018.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174287PMC
October 2018

Heterozygous WNT1 variant causing a variable bone phenotype.

Am J Med Genet A 2018 11 24;176(11):2419-2424. Epub 2018 Sep 24.

University of California, San Diego, La Jolla, California.

Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein, we report a third-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A WNT1 variant (c. 1051 > C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional nonosseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in preadolescence). This case demonstrates the variability of bone phenotype conferred by a WNT1 variant and extends the spectrum of bone phenotypes associated with heterozygous WNT1 mutations.
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http://dx.doi.org/10.1002/ajmg.a.40347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289778PMC
November 2018

Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination, and Arthrogryposis.

J Child Neurol 2018 09 8;33(10):642-650. Epub 2018 Jun 8.

1 Department of Neurology, Children's National Health System, Washington, DC, USA.

Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such individuals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G>C (p.Arg388Pro) and compound heterozygous c.967T>C (p.Cys323Arg) and c.319C>T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.
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http://dx.doi.org/10.1177/0883073818776157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800098PMC
September 2018

Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy.

Am J Med Genet A 2018 06 25;176(6):1443-1448. Epub 2018 Apr 25.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Early-onset epileptic encephalopathies (EOEEs) are a genetically heterogeneous collection of severe epilepsies often associated with psychomotor regression. Mutations in SZT2, a known seizure threshold regulator gene, are a newly identified cause of EOEE. We present an individual with EOEE, macrocephaly, and developmental regression with compound heterozygous mutations in SZT2 as identified by whole exome sequencing. Serial imaging characterized the novel finding of progressive loss of central myelination. This case expands our clinical understanding of the SZT2-phenotype and emphasizes the role of this gene in the diagnostic investigation for EOEE and leukoencephalopathies.
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http://dx.doi.org/10.1002/ajmg.a.38717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025690PMC
June 2018

Congenital sodium diarrhea and chorioretinal coloboma with optic disc coloboma in a patient with biallelic SPINT2 mutations, including p.(Tyr163Cys).

Am J Med Genet A 2018 04;176(4):997-1000

Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, California.

Congenital sodium diarrhea is a rare and life-threatening disorder characterized by a severe, secretory diarrhea containing high concentrations of sodium, leading to hyponatremia and metabolic acidosis. It may occur in isolation or in association with systemic features such as facial dysmorphism, choanal atresia, imperforate anus, and corneal erosions. Mutations in the serine protease inhibitor, Kunitz-Type 2 (SPINT2) gene have been associated with congenital sodium diarrhea and additional syndromic features. We present a child with congenital sodium diarrhea, cleft lip and palate, corneal erosions, optic nerve coloboma, and intermittent exotropia who was found to have biallelic mutations in SPINT2. One mutation, c.488A > G, predicting p.(Tyr163Cys), has been previously associated with a syndromic form of congenital sodium diarrhea. The other mutation, c.166_167dupTA, predicting p.(Asn57Thrfs*24) has not previously been reported and is likely a novel pathogenic variant for this disorder. We found only one other report of an optic nerve coloboma associated with SPINT2 mutations and this occurred in a patient with congenital tufting enteropathy. Our patient confirms an association of ocular coloboma with presumed loss of SPINT2 function.
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http://dx.doi.org/10.1002/ajmg.a.38637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875720PMC
April 2018