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RESEARCH PRODUCT
Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants
Ji-eun YoonArjun KrishnanMarie VincentMarco FicheraClaire BeneteauErik A. SistermansNathalie MarleLuana MandaràSau Wai CheungR. Frank KooyTeresa MattinaRachel L. KemberMathilde NizonJill A. RosenfeldAlexandre ReymondBertrand IsidorSophie BlessonJean-hubert CabergCindy SkinnerEmanuela AvolaCharles PerrinePaolo PronteraSusan ZeesmanMałgorzata J.m. NowaczykKate PopeLucilla PizzoDavid J. AmorBoris KerenMatthew JensenKatrin MännikKatrin MännikPatrick CallierPawel StankiewiczDamian PazuchanicsEls VoorhoeveOrnella GalesiJoris AndrieuxLucia CastigliaAnne Laure Mosca-boidronMathilde LefebvreCharles E. SchwartzSanthosh GirirajanElizabeth MccreadyAnke Van DijckSandra MercierMaja BucanCorrado RomanoLaurence FaivreFrancesca MariDominique Martin-coignardVijay KumarAlessandra RenieriAndrew PolyakAndrew PolyakEmily HuberCédric Le CaignecAurora CurròOlivier Pichonsubject
MaleParents0301 basic medicineProbandNeuronalGenetic Carrier Screening16p11.2 deletion030105 genetics & heredityCognitionFamily historyNeural Cell Adhesion MoleculesGenetics (clinical)Exome sequencingSequence DeletionGeneticsGenetic Carrier ScreeningPhenotypePenetrancePedigreePhenotypeAutistic Disorder/genetics; Autistic Disorder/physiopathology; Cell Adhesion Molecules Neuronal/genetics; Chromosomes Human Pair 16/genetics; Cognition/physiology; DNA Copy Number Variations/genetics; Female; Gene Expression Regulation/genetics; Genetic Background; Genetic Carrier Screening; Humans; Male; Methyltransferases/genetics; Nerve Tissue Proteins/genetics; Parents; Pedigree; Phenotype; Proteins/genetics; Sequence Deletion/genetics; Siblings; 16p11.2 deletion; CNV; autism; modifier; phenotypic variabilityFemaleGenetic BackgroundHumanDNA Copy Number VariationsCell Adhesion Molecules NeuronalCNVautismNerve Tissue ProteinsBiologyChromosomesArticle03 medical and health sciencesmental disordersmedicineHumansAutistic DisorderBiologyGenemodifierPair 16SiblingsCalcium-Binding ProteinsProteinsMethyltransferasesmedicine.disease16p11.2 deletion; autism; CNV; modifier; phenotypic variability; Genetics (clinical)Cytoskeletal Proteins030104 developmental biologyGene Expression Regulation[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsAutismphenotypic variabilityHuman medicine16p11.2 deletion; autism; CNV; modifier; phenotypic variability; Autistic Disorder; Cell Adhesion Molecules Neuronal; Chromosomes Human Pair 16; Cognition; DNA Copy Number Variations; Female; Gene Expression Regulation; Genetic Background; Humans; Male; Methyltransferases; Nerve Tissue Proteins; Parents; Pedigree; Phenotype; Proteins; Sequence Deletion; Siblings; Genetic Carrier ScreeningCell Adhesion MoleculesChromosomes Human Pair 16Transcription Factorsdescription
Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. Results: The number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-04-01 | Genetics in Medicine |