Publications by authors named "Sheng Chih Jin"

55 Publications

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Am J Hum Genet 2021 Oct;108(10):2006-2016

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.003DOI Listing
October 2021

PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets.

Trends Neurosci 2021 Oct 5. Epub 2021 Oct 5.

Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.
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http://dx.doi.org/10.1016/j.tins.2021.08.007DOI Listing
October 2021

Biallelic AOPEP Loss-of-Function Variants Cause Progressive Dystonia with Prominent Limb Involvement.

Mov Disord 2021 Oct 1. Epub 2021 Oct 1.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging.

Objective: We sought to expand the catalogue of monogenic etiologies for isolated dystonia.

Methods: After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles.

Results: Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696_697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism.

Conclusions: Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28804DOI Listing
October 2021

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy.

Genet Med 2021 Aug 12. Epub 2021 Aug 12.

Texas Children's Hospital, Houston, TX, USA.

Purpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.

Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher.

Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores -0.95 to -5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function.

Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
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http://dx.doi.org/10.1038/s41436-021-01291-xDOI Listing
August 2021

Mutation in Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability.

Neurol Genet 2021 Aug 29;7(4):e602. Epub 2021 Jul 29.

Pediatric Movement Disorders Program (S.A.L., S.B., J.H., J.L., S.R.P.-L., M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital; Departments of Child Health, Neurology, Genetics and Cellular & Molecular Medicine (S.A.L., S.B., J.L., S.R.P.-L., M.C.K.), University of Arizona College of Medicine; Division of Neuroradiology (P.C.), Department of Radiology, Phoenix Children's Hospital, AZ; Programs in Neuroscience and Molecular & Cellular Biology (A.H., A.M.), Arizona State University, Tempe; and Department of Genetics (S.C.J.), Washington University, St. Louis, MO; Department of Genetics (K.B.), Yale University, New Haven, CT.

Objective: To determine whether mutations reported for can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models.

Methods: We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a model.

Results: Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in .

Conclusions: Our findings support a functional expansion of this gene to a role in motor dysfunction. Although mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.
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http://dx.doi.org/10.1212/NXG.0000000000000602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323736PMC
August 2021

Genomics of human congenital hydrocephalus.

Childs Nerv Syst 2021 Jul 7. Epub 2021 Jul 7.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.
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http://dx.doi.org/10.1007/s00381-021-05230-8DOI Listing
July 2021

Molecular Genetics and Complex Inheritance of Congenital Heart Disease.

Genes (Basel) 2021 06 30;12(7). Epub 2021 Jun 30.

Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA.

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
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http://dx.doi.org/10.3390/genes12071020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307500PMC
June 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Brain 2021 06;144(5):1422-1434

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
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http://dx.doi.org/10.1093/brain/awab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219359PMC
June 2021

Recessive Mutation Leads to Intellectual Disability, Epilepsy, and Spastic Cerebral Palsy.

Neurol Genet 2021 Jun 22;7(3):e583. Epub 2021 Apr 22.

Pediatric Movement Disorders Program (S.B., B.S.G., M.C.K.), Barrow Neurological Institute, Phoenix Children's Hospital, AZ; Departments of Child Health (S.B., B.S.G., M.C.K.), Neurology, Genetics, and Cellular & Molecular Medicine, University of Arizona College of Medicine Phoenix, Phoenix, AZ; Iranian Center of Neurological Research (A.T., H.D.), Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Department of Genetics (S.C.J.), Washington University School of Medicine, St. Louis, MO; Student Research Committee (E.A.), School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Genetics Research Center (S.F.), University of Social Welfare and Rehabilitation Sciences, Tehran, Iran; Department of Genetics (K.B.), Yale University, New Haven, CT; and Department of Paediatrics (M.C.F.), Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1212/NXG.0000000000000583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077768PMC
June 2021

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

Clin Genet 2021 08 2;100(2):176-186. Epub 2021 Jun 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.
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http://dx.doi.org/10.1111/cge.13973DOI Listing
August 2021

Analysis workflow to assess genetic variants from human whole-exome sequencing.

STAR Protoc 2021 Mar 10;2(1):100383. Epub 2021 Mar 10.

Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.

Here, we present a protocol to analyze genetic variants derived from the whole-exome sequencing (WES) of proband-parent trios. We provide stepwise instructions for using existing pipelines to call mutations (DNMs) and determine whether the observed number of such mutations is enriched relative to the expected number. This protocol may be extended to any human disease trio-based cohort. Cohort size is a limiting determinant to the discovery of high-confidence pathogenic DNMs. For complete details on the use and execution of this protocol, please refer to Dong et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960548PMC
March 2021

Variant recurrence confirms the existence of a FBXO31-related spastic-dystonic cerebral palsy syndrome.

Ann Clin Transl Neurol 2021 04 6;8(4):951-955. Epub 2021 Mar 6.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by prominent motor dysfunction.
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http://dx.doi.org/10.1002/acn3.51335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045898PMC
April 2021

Insights From Genetic Studies of Cerebral Palsy.

Front Neurol 2020 21;11:625428. Epub 2021 Jan 21.

Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, United States.

Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known environmental risk factors. We discuss the overlap of CP-associated genes with other neurodevelopmental disorders and related movement disorders. We revisit diagnostic criteria for CP and discuss how identification of genetic etiologies does not preclude CP as an appropriate diagnosis. The identification of genetic etiologies improves our understanding of the neurobiology of CP, providing opportunities to study CP pathogenesis and develop mechanism-based interventions.
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http://dx.doi.org/10.3389/fneur.2020.625428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859255PMC
January 2021

Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.

JAMA Cardiol 2021 Apr;6(4):457-462

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions.

Objective: To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants.

Design, Setting, And Participants: This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019.

Exposures: Presence of rare (allele frequency, <1 × 10-5) loss-of-function (LoF) variants in cancer risk genes.

Main Outcomes And Measures: Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer-Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants.

Results: A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10-12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10-16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and extracardiac anomalies (248 of 1482 individuals [16.7%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.59 [95% CI, 1.37-1.85]; P = 1.3 × 10-10) and/or neurodevelopmental delay (209 of 1393 individuals [15.0%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.40 [95% CI, 1.19-1.64]; P = 9.6 × 10-6).

Conclusions And Relevance: Genotypes of CHD may account for increased cancer risks. In this cohort, damaging variants were prominent in the 216 genes that predominantly encode regulatory proteins. Consistent with their fundamental developmental functions, patients with CHD and damaging variants in these genes often had extracardiac manifestations. These data may also implicate cancer risk genes that are repeatedly varied in patients with unexplained CHD as CHD genes.
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http://dx.doi.org/10.1001/jamacardio.2020.4947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578917PMC
April 2021

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

iScience 2020 Oct 11;23(10):101552. Epub 2020 Sep 11.

Yale Center for Genome Analysis, West Haven, CT, USA.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.
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http://dx.doi.org/10.1016/j.isci.2020.101552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554653PMC
October 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Nat Genet 2020 10 28;52(10):1046-1056. Epub 2020 Sep 28.

Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.
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http://dx.doi.org/10.1038/s41588-020-0695-1DOI Listing
October 2020

Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.

Genet Med 2020 06 26;22(6):1061-1068. Epub 2020 Feb 26.

Institute of Human Genetics, Faculty of Medicine, Technical University München, Munich, Germany.

Purpose: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum.

Methods: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR.

Results: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified.

Conclusion: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
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http://dx.doi.org/10.1038/s41436-020-0768-7DOI Listing
June 2020

Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in .

Front Cell Neurosci 2019 26;13:425. Epub 2019 Sep 26.

Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, United States.

Background: encodes the α3 subunit of the Na/K ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in have never been associated with any human disease. deficiency in zebrafish results in hydrocephalus; however, no known association exists between and human congenital hydrocephalus (CH).

Methods: We utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize expression during brain development.

Results: We identified two germline mutations in (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient's unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain.

Conclusion: These data provide the first evidence of a recessive human phenotype associated with mutations in , and implicate impaired Na/K ATPase function in the pathogenesis of CH.
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http://dx.doi.org/10.3389/fncel.2019.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775207PMC
September 2019

SLC12A ion transporter mutations in sporadic and familial human congenital hydrocephalus.

Mol Genet Genomic Med 2019 09 8;7(9):e892. Epub 2019 Aug 8.

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.

Background: Congenital hydrocephalus (CH) is a highly morbid disease that features enlarged brain ventricles and impaired cerebrospinal fluid homeostasis. Although early linkage or targeted sequencing studies in large multigenerational families have localized several genes for CH, the etiology of most CH cases remains unclear. Recent advances in whole exome sequencing (WES) have identified five new bona fide CH genes, implicating impaired regulation of neural stem cell fate in CH pathogenesis. Nonetheless, in the majority of CH cases, the pathological etiology remains unknown, suggesting more genes await discovery.

Methods: WES of family members of a sporadic and familial form of severe L1CAM mutation-negative CH associated with aqueductal stenosis was performed. Rare genetic variants were analyzed, prioritized, and validated. De novo copy number variants (CNVs) were identified using the XHMM algorithm and validated using qPCR. Xenopus oocyte experiments were performed to access mutation impact on protein function and expression.

Results: A novel inherited protein-damaging mutation (p.Pro605Leu) in SLC12A6, encoding the K -Cl cotransporter KCC3, was identified in both affected members of multiplex kindred CHYD110. p.Pro605 is conserved in KCC3 orthologs and among all human KCC paralogs. The p.Pro605Leu mutation maps to the ion-transporting domain, and significantly reduces KCC3-dependent K transport. A novel de novo CNV (deletion) was identified in SLC12A7, encoding the KCC3 paralog and binding partner KCC4, in another family (CHYD130) with sporadic CH.

Conclusion: These findings identify two novel, related genes associated with CH, and implicate genetically encoded impairments in ion transport for the first time in CH pathogenesis.
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http://dx.doi.org/10.1002/mgg3.892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732308PMC
September 2019

Mutations in and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.

Proc Natl Acad Sci U S A 2019 07 10;116(30):15116-15121. Epub 2019 Jul 10.

Department of Genetics, Yale University School of Medicine, New Haven, CT 06510;

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation ( = 4.0 × 10); additionally, a rare damaging mutation in , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant ( = 8.2 × 10). Three probands had rare damaging mutations in , , or , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier , and , encoding catenin α-1. These findings establish as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.
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http://dx.doi.org/10.1073/pnas.1902041116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660739PMC
July 2019

Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility.

Proc Natl Acad Sci U S A 2019 07 24;116(28):14049-14054. Epub 2019 Jun 24.

Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510;

Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40, and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment 6.01, = 1.67 × 10), some of whom had abnormal laterality associated with ciliary dysfunction. In , knockdown of and results in abnormal heart looping, defective development of left-right (LR) asymmetry, and impaired cilia motility. Rnf20, Rnf40, and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and nonciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rnf20 knockdown results in decreased levels of mRNA in , and exogenous can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.
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http://dx.doi.org/10.1073/pnas.1808341116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628794PMC
July 2019

Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen.

PLoS Pathog 2019 04 5;15(4):e1007704. Epub 2019 Apr 5.

Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Typhoid toxin is a virulence factor for Salmonella Typhi and Paratyphi, the cause of typhoid fever in humans. This toxin has a unique architecture in that its pentameric B subunit, made of PltB, is linked to two enzymatic A subunits, the ADP ribosyl transferase PltA and the deoxyribonuclease CdtB. Typhoid toxin is uniquely adapted to humans, recognizing surface glycoprotein sialoglycans terminated in acetyl neuraminic acid, which are preferentially expressed by human cells. The transport pathway to its cellular targets followed by typhoid toxin after receptor binding is currently unknown. Through a genome-wide CRISPR/Cas9-mediated screen we have characterized the mechanisms by which typhoid toxin is transported within human cells. We found that typhoid toxin hijacks specific elements of the retrograde transport and endoplasmic reticulum-associated degradation machineries to reach its subcellular destination within target cells. Our study reveals unique and common features in the transport mechanisms of bacterial toxins that could serve as the bases for the development of novel anti-toxin therapeutic strategies.
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http://dx.doi.org/10.1371/journal.ppat.1007704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469816PMC
April 2019

EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease.

Trends Mol Med 2019 04 25;25(4):265-286. Epub 2019 Feb 25.

Department of Neurosurgery, Yale School of Medicine, New Haven CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven CT, USA. Electronic address:

Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.
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http://dx.doi.org/10.1016/j.molmed.2019.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456402PMC
April 2019

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Neuron 2019 02 18;101(3):429-443.e4. Epub 2018 Dec 18.

Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.
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http://dx.doi.org/10.1016/j.neuron.2018.11.041DOI Listing
February 2019
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