2024
Case report: Novel variants cause developmental and epileptic encephalopathy in three unrelated families from Mali
Bamba S, Sidibé L, Diallo S, Cissé L, Dembélé K, Yalcouyé A, Ji W, Dembélé M, Diarra S, Maiga A, Traoré O, Diallo S, Mefoung S, Touré A, Koné A, Jeffries L, Guinto C, Mis E, Fischbeck K, Khokha M, Lakhani S, Landouré G. Case report: Novel variants cause developmental and epileptic encephalopathy in three unrelated families from Mali. Frontiers In Genetics 2024, 15: 1412442. DOI: 10.3389/fgene.2024.1412442.Peer-Reviewed Original ResearchWhole-exome sequencingGenetic basisIdentified rare variantsIn silico prediction analysisCompound heterozygous variantsPutative variantsIn silico toolsACMG criteriaExome sequencingProtein structureNovel variantsEpileptic encephalopathyAssess pathogenicityHeterozygous variantsRare variantsHomozygous variantSub-Saharan AfricaDisease mechanismsAssociated with earlier onsetRefractory to antiepileptic medicationsResistant to treatmentGroup of neurological disordersMalian familyEarly-onset seizuresPotential clinical implicationsGenetic profile of progressive myoclonic epilepsy in Mali reveals novel findings
Cissé L, Bamba S, Diallo S, Ji W, Dembélé M, Yalcouyé A, Coulibaly T, Traoré I, Jeffries L, Diarra S, Maiga A, Diallo S, Nimaga K, Touré A, Traoré O, Kotioumbé M, Mis E, Cissé C, Guinto C, Fischbeck K, Khokha M, Lakhani S, Landouré G. Genetic profile of progressive myoclonic epilepsy in Mali reveals novel findings. Frontiers In Neurology 2024, 15: 1455467. PMID: 39385815, PMCID: PMC11461190, DOI: 10.3389/fneur.2024.1455467.Peer-Reviewed Original ResearchWhole-exome sequencingACMG criteriaProgressive myoclonic epilepsyProtein 3D structuresHomozygous missense variantRecessive inheritance patternCADD scoresAutosomal recessive inheritance patternSequence variantsMissense variantsGenomic researchExome sequencingGenetic analysisGenetic studiesPathogenic variantsPedigree analysisGenetic epidemiologyGenetic researchGenetic profileHeterogeneous neurological disordersInheritance patternSporadic formsACMGGroup of neurological disordersMyoclonic epilepsyCC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow
Kim A, Sakin I, Viviano S, Tuncel G, Aguilera S, Goles G, Jeffries L, Ji W, Lakhani S, Kose C, Silan F, Oner S, Kaplan O, Group M, Ergoren M, Mishra-Gorur K, Gunel M, Sag S, Temel S, Deniz E. CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow. Life Science Alliance 2024, 7: e202402708. PMID: 39168639, PMCID: PMC11339347, DOI: 10.26508/lsa.202402708.Peer-Reviewed Original ResearchConceptsDevelopmental disabilitiesIntellectual disabilityPatient-derived fibroblastsMidbrain regionsBrain developmentDefective ciliogenesisCSF circulationDisabilityCSF flowAbnormal CSF flowNervous system developmentMutant tadpolesCiliated tissuesMultiple model systemsVariant functionPronephric ductUnrelated familiesCC2D1AExpression patternsCiliogenesisRenal dysplasiaLeft-right organizerFunctional analysisDisease mechanismsBrainExome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders
Bibi A, Ji W, Jeffries L, Zerillo C, Konstantino M, Mis E, Khursheed F, Khokha M, Lakhani S, Malik S. Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders. American Journal Of Medical Genetics Part C Seminars In Medical Genetics 2024, e32103. PMID: 39152716, DOI: 10.1002/ajmg.c.32103.Peer-Reviewed Original ResearchExome sequencingConsanguineous Pakistani familyDisease-causing genesFamily segregation analysisAssociated with phenotypesAffected individualsAccurate molecular diagnosisACMG criteriaCandidate variantsGenomic studiesPakistani familyGenomic researchGenetic heterogeneityNovel variantsSegregation analysisConsanguineous familyGenetic variantsNeurodevelopmental disordersHomozygous variantNeuromuscular disordersMiddle-income countriesMolecular diagnosisExomeES dataClinical phenotypeUnraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan
Azab B, Aburizeg D, Shaaban S, Ji W, Mustafa L, Isbeih N, Al-Akily A, Mohammad H, Jeffries L, Khokha M, Lakhani S, Al-Ammouri I. Unraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan. Scientific Reports 2024, 14: 15141. PMID: 38956129, PMCID: PMC11219879, DOI: 10.1038/s41598-024-64921-9.Peer-Reviewed Original ResearchConceptsExome sequencingSarcomere-related genesMitochondrial-related diseasesAt-risk family membersGenetic architectureGenetic landscapePathogenic variantsGene panelPediatric cardiomyopathyMolecular underpinningsGenetic testingPhenocopiesSarcomeric cardiomyopathiesGenesSequenceStorage disorderFamily membersAt-riskVariantsEarly interventionExomeFamilyGlycogen storage disorderHypertrophic cardiomyopathyCardiomyopathy
2023
CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability
Deniz E, Pasha M, Guerra M, Viviano S, Ji W, Konstantino M, Jeffries L, Lakhani S, Medne L, Skraban C, Krantz I, Khokha M. CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability. Developmental Biology 2023, 499: 75-88. PMID: 37172641, PMCID: PMC10373286, DOI: 10.1016/j.ydbio.2023.04.006.Peer-Reviewed Original ResearchConceptsLeft-right organizerCilia stabilityLeft-right patterningCongenital heart disease genesApical surfaceCell apical surfaceLive confocal imagingLeftward fluid flowHeart disease genesRecessive missense mutationLethal birth defectMotile monociliaProtein familyEarly embryogenesisMulticiliated cellsCiliary axonemeDisease genesFrog embryosGenetic underpinningsWhole-exome sequencingMissense mutationsConfocal imagingEmbryosCiliaCongenital heart disease
2022
A retrospective cohort analysis of the Yale pediatric genomics discovery program
Al‐Ali S, Jeffries L, Faustino EVS, Ji W, Mis E, Konstantino M, Zerillo C, Jiang Y, Spencer‐Manzon M, Bale A, Zhang H, McGlynn J, McGrath JM, Tremblay T, Brodsky NN, Lucas CL, Pierce R, Deniz E, Khokha MK, Lakhani SA. A retrospective cohort analysis of the Yale pediatric genomics discovery program. American Journal Of Medical Genetics Part A 2022, 188: 2869-2878. PMID: 35899841, PMCID: PMC9474639, DOI: 10.1002/ajmg.a.62918.Peer-Reviewed Original ResearchConceptsRetrospective cohort analysisNext-generation sequencingCohort analysisSystem abnormalitiesImmune system abnormalitiesCardiovascular system abnormalitiesFunctional molecular analysesNovel genesPrecise molecular diagnosisClinical characteristicsFurther genetic evaluationDiscovery programsComplex patientsMultisystem diseaseDisease genesPediatric providersRare genetic diseaseNew diagnosisPhenotype relationshipsPatientsGenetic diseasesMolecular analysisDiagnosisParticipant demographicsNGS resultsTBX5 variant with the novel phenotype of mixed-type total anomalous pulmonary venous return in Holt-Oram Syndrome and variable intrafamilial heart defects
Azab B, Aburizeg D, Ji W, Jeffries L, Isbeih NJ, Al-Akily AS, Mohammad H, Abu Osba Y, Shahin MA, Dardas Z, Hatmal MM, Al-Ammouri I, Lakhani S. TBX5 variant with the novel phenotype of mixed-type total anomalous pulmonary venous return in Holt-Oram Syndrome and variable intrafamilial heart defects. Molecular Medicine Reports 2022, 25: 210. PMID: 35514310, PMCID: PMC9133962, DOI: 10.3892/mmr.2022.12726.Peer-Reviewed Original ResearchConceptsHolt-Oram syndromeMolecular etiologyT-box domainWild-type proteinT-box transcription factorGenetic investigationsTrio-based whole-exome sequencingNonsense variantTranscription factorsIntrafamilial levelTBX5 proteinNovel phenotypesProtein's abilityFirst genetic investigationMutant dimersNon-syndromic presentationsProtein modelingWhole-exome sequencingComplete phenotypingSubsequent genetic investigationsTbx5Novel associationsPowerful approachWide phenotypic spectrumNon-covalent bonds
2021
Correction: Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons
Runge K, Mathieu R, Bugeon S, Lafi S, Beurrier C, Sahu S, Schaller F, Loubat A, Herault L, Gaillard S, Pallesi-Pocachard E, Montheil A, Bosio A, Rosenfeld JA, Hudson E, Lindstrom K, Mercimek-Andrews S, Jeffries L, van Haeringen A, Vanakker O, Van Hecke A, Amrom D, Küry S, Ratner C, Jethva R, Gamble C, Jacq B, Fasano L, Santpere G, Lorente-Galdos B, Sestan N, Gelot A, Giacuzz S, Goebbels S, Represa A, Cardoso C, Cremer H, de Chevigny A. Correction: Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons. Molecular Psychiatry 2021, 26: 7852-7852. PMID: 34282265, PMCID: PMC8873008, DOI: 10.1038/s41380-021-01234-7.Peer-Reviewed Original ResearchDisruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons
Runge K, Mathieu R, Bugeon S, Lafi S, Beurrier C, Sahu S, Schaller F, Loubat A, Herault L, Gaillard S, Pallesi-Pocachard E, Montheil A, Bosio A, Rosenfeld JA, Hudson E, Lindstrom K, Mercimek-Andrews S, Jeffries L, van Haeringen A, Vanakker O, Van Hecke A, Amrom D, Küry S, Ratner C, Jethva R, Gamble C, Jacq B, Fasano L, Santpere G, Lorente-Galdos B, Sestan N, Gelot A, Giacuzz S, Goebbels S, Represa A, Cardoso C, Cremer H, de Chevigny A. Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons. Molecular Psychiatry 2021, 26: 6125-6148. PMID: 34188164, PMCID: PMC8760061, DOI: 10.1038/s41380-021-01179-x.Peer-Reviewed Original ResearchConceptsLayer 5 neuronsKO miceForebrain glutamatergic neuronsTranscription factor NeuroD2Forebrain excitatory neuronsNeurodevelopmental disordersAutism spectrum disorderCortical projection neuronsPatch-clamp recordingsIntellectual disabilitySocial interaction deficitsSpontaneous seizuresCerebral cortexGlutamatergic neuronsSpine densityProjection neuronsIntrinsic excitabilityNervous system developmentNeuronal excitabilityExcitatory neuronsJuvenile miceBulk RNA sequencingSynaptic functionNeurobehavioral featuresDysregulated expressionFunctional testing for variant prioritization in a family with long QT syndrome
Najari Beidokhti M, Bertalovitz AC, Ji W, McCormack J, Jeffries L, Sempou E, Khokha MK, McDonald TV, Lakhani SA. Functional testing for variant prioritization in a family with long QT syndrome. Molecular Genetics And Genomics 2021, 296: 823-836. PMID: 33876311, DOI: 10.1007/s00438-021-01780-3.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAMP-Activated Protein KinasesDNA Mutational AnalysisElectrocardiographyERG1 Potassium ChannelExome SequencingFamilyFemaleGenetic TestingHeart Function TestsHEK293 CellsHumansKCNQ1 Potassium ChannelLong QT SyndromeMiddle AgedMutationPedigreePhenotypePolymerase Chain ReactionPolymorphism, Single NucleotideProtein Serine-Threonine KinasesConceptsWhole-exome sequencingFunctional characterizationSilico analysisPrecise genetic etiologyHeterologous expression systemNext-generation sequencing platformsNovel genetic variantsDeleterious phenotypesFunction phenotypesExpression systemSequencing platformsSecond individualHeritable diseaseVariant prioritizationGenetic variantsLong QT syndromeExome sequencingGenetic etiologyGenetic settingClinical genetics settingPhenotypeFamilyGene panelFamily membersVariantsExpansion of NEUROD2 phenotypes to include developmental delay without seizures
Mis EK, Sega AG, Signer RH, Cartwright T, Ji W, Martinez‐Agosto J, Nelson SF, Palmer CGS, Lee H, Mitzelfelt T, Konstantino M, Network U, Jeffries L, Khokha MK, Marco E, Martin MG, Lakhani SA. Expansion of NEUROD2 phenotypes to include developmental delay without seizures. American Journal Of Medical Genetics Part A 2021, 185: 1076-1080. PMID: 33438828, PMCID: PMC8212414, DOI: 10.1002/ajmg.a.62064.Peer-Reviewed Original ResearchConceptsDevelopmental delayEarly-onset seizuresDe novo heterozygous variantsNovo heterozygous variantsDifferentiation factor 2Xenopus laevis tadpolesHeterozygous variantsSeizuresNeuronal differentiationParental studiesFunctional testingMissense variantsPatient variantsFunctional evidenceFactor 2Vivo assaysLaevis tadpolesVariant pathogenicityFunction effectsAdolescentsVariants
2020
The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence
Mis EK, Al‐Ali S, Ji W, Spencer‐Manzon M, Konstantino M, Khokha MK, Jeffries L, Lakhani SA. The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence. American Journal Of Medical Genetics Part A 2020, 182: 2291-2296. PMID: 32812332, DOI: 10.1002/ajmg.a.61783.Peer-Reviewed Original ResearchConceptsFetal akinesia deformation sequenceArthrogryposis multiplex congenitaCohort of patientsScope of illnessPulmonary hypoplasiaAdditional patientsClinical featuresNeonatal supportNervous system developmentMultiplex congenitaCongenital contracturesPatientsHeterogenous conditionRecessive variantsPatient variantsFunctional evidenceCohortNovel variantsContractureFunctional dataSyndromeHypoplasiaIllnessVariantsFindingsDYNC1H1‐related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants
Amabile S, Jeffries L, McGrath JM, Ji W, Spencer‐Manzon M, Zhang H, Lakhani SA. DYNC1H1‐related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants. American Journal Of Medical Genetics Part A 2020, 182: 2049-2057. PMID: 32656949, DOI: 10.1002/ajmg.a.61729.Peer-Reviewed Original ResearchConceptsSpinal muscular atrophyIntellectual disabilityUnrelated patientsSingle-center experienceNew unrelated patientsCenter experienceDYNC1H1 geneCNS disordersCombined disordersCortical developmentDisease-causing variantsVariable syndromeNeuromuscular diseaseNeuromuscular phenotypePatientsMuscular atrophyHeterozygous variantsDYNC1H1Medical literatureCharcot-MarieDisordersType 20Novel variantsPhenotypeReportDLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes
Marquez J, Mann N, Arana K, Deniz E, Ji W, Konstantino M, Mis EK, Deshpande C, Jeffries L, McGlynn J, Hugo H, Widmeier E, Konrad M, Tasic V, Morotti R, Baptista J, Ellard S, Lakhani SA, Hildebrandt F, Khokha MK. DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. Journal Of Medical Genetics 2020, 58: 453-464. PMID: 32631816, PMCID: PMC7785698, DOI: 10.1136/jmedgenet-2019-106805.Peer-Reviewed Original ResearchConceptsLoss of ciliaPatient tissuesPatient variantsCongenital heart diseaseMultiple organ systemsMultiple congenital anomaliesDLG5 variantsVariety of pathologiesNephrotic syndromeHeart diseaseCongenital anomaliesRespiratory tractKidney tissueOrgan systemsCystic kidneysPatient phenotypesKidneyDiseaseLimb abnormalitiesUnrelated familiesRescue experimentsCraniofacial malformationsCilia dysfunctionTissue-specific manifestationsTissueA novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype
AbuBakr F, Jeffries L, Ji W, McGrath JM, Lakhani SA. A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype. Molecular Case Studies 2020, 6: mcs.a005207. PMID: 32299812, PMCID: PMC7304360, DOI: 10.1101/mcs.a005207.Peer-Reviewed Original ResearchConceptsCardiospondylocarpofacial syndromePathogenic variantsValvular heart diseaseDistinctive cutaneous findingsLikely pathogenic variantsCutaneous findingsFlexion contractureHeart diseaseSecond toePatientsShort statureGrowth factorProtein kinase kinase kinase 7Facial dysmorphismSyndrome phenotypeMissense variantsSyndromeKinase 7Kinase 1Novel variantsSixth variantSplice variantsPhenotypeFrame deletionInflammationFamilial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants
Landim-Vieira M, Johnston JR, Ji W, Mis EK, Tijerino J, Spencer-Manzon M, Jeffries L, Hall EK, Panisello-Manterola D, Khokha MK, Deniz E, Chase PB, Lakhani SA, Pinto JR. Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants. Frontiers In Physiology 2020, 10: 1612. PMID: 32038292, PMCID: PMC6990120, DOI: 10.3389/fphys.2019.01612.Peer-Reviewed Original ResearchCardiac muscle preparationsIsometric forcePatient variantsEarly-onset DCMDilated Cardiomyopathy AssociatedCompound heterozygous variantsSteady-state isometric forceCardiomyopathy AssociatedContractile functionMuscle preparationsCardiomyopathy phenotypeHeterozygous variantsCardiac phenotypeMyofilament CaSarcomeric genesFurther studies
2019
Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure
Criscione J, Ji W, Jeffries L, McGrath JM, Soloway S, Pusztai L, Lakhani S. Identification of a novel MYOC variant in a Hispanic family with early-onset primary open-angle glaucoma with elevated intraocular pressure. Molecular Case Studies 2019, 5: a004374. PMID: 31653660, PMCID: PMC6913140, DOI: 10.1101/mcs.a004374.Peer-Reviewed Original ResearchConceptsPrimary open-angle glaucomaEarly-onset primary open-angle glaucomaOpen-angle glaucomaGenetic testingElevated intraocular pressureJuvenile-onset primary open-angle glaucomaFurther genetic testingAutosomal dominant patternFemale patientsIntraocular pressureIrreversible blindnessFamily historyEye disordersMYOC variantsMyocilin geneGlaucomaPOAG phenotypeHispanic familiesOlfactomedin domainPrevious findingsDominant patternVariant segregatesMost casesPatientsEtiologySiblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum
Kiraly-Borri C, Jevon G, Ji W, Jeffries L, Ricciardi JL, Konstantino M, Ackerman KG, Lakhani SA. Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum. Molecular Case Studies 2019, 5: a003699. PMID: 30819764, PMCID: PMC6549552, DOI: 10.1101/mcs.a003699.Peer-Reviewed Original ResearchConceptsPrimary pulmonary hypoplasiaPulmonary hypoplasiaPhenotypic spectrumEvidence of cardiomyopathyPremature ovarian insufficiencyAbsence of cardiomyopathyCompound heterozygous variantsWhole-exome sequencingOvarian insufficiencyAARS2 geneCompound HeterozygousHeterozygous variantsCardiomyopathyNewborn siblingsCarrier statusFurther delineationHypoplasiaUnaffected siblingsMitochondrial cardiomyopathySiblingsFirst reportLeukoencephalopathyRefractory Infantile Chronic Diarrhea and Failure to Thrive in a 6-Month-Old Boy With a Complex Past Medical History
Okafor D, AlRabadi L, Alper A, Jeffries L, McGrath J, Porto AF. Refractory Infantile Chronic Diarrhea and Failure to Thrive in a 6-Month-Old Boy With a Complex Past Medical History. Clinical Pediatrics 2019, 58: 707-710. PMID: 30788983, DOI: 10.1177/0009922819832034.Peer-Reviewed Original Research