Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

Purpose:Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing.Methods:Family-based exome sequencing included whole-exome sequencing followed by family inheritance−based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes.Results:A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy.Conclusion:Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.Genet Med 17 7, 578–586.

[1]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[2]  S. Blanton,et al.  De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis , 2013, Human Genetics.

[3]  K. Boycott,et al.  Rare-disease genetics in the era of next-generation sequencing: discovery to translation , 2013, Nature Reviews Genetics.

[4]  Jacqueline K. White,et al.  Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. , 2012, American journal of human genetics.

[5]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[6]  Adam Yao,et al.  PrimerZ: streamlined primer design for promoters, exons and human SNPs , 2007, Nucleic Acids Res..

[7]  Naomichi Matsumoto,et al.  De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. , 2013, American journal of human genetics.

[8]  J. Opitz,et al.  The effect of Mendelian disease on human health: a measurement. , 1985, American journal of medical genetics.

[9]  Damian Smedley,et al.  Improved exome prioritization of disease genes through cross-species phenotype comparison , 2014, Genome research.

[10]  L. Vissers,et al.  Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. , 2012, American journal of human genetics.

[11]  P. Bork,et al.  A method and server for predicting damaging missense mutations , 2010, Nature Methods.

[12]  Leslie G Biesecker,et al.  Diagnostic clinical genome and exome sequencing. , 2014, The New England journal of medicine.

[13]  S. Henikoff,et al.  Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm , 2009, Nature Protocols.

[14]  Rena A. Godfrey,et al.  The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases , 2011, Genetics in Medicine.

[15]  L. Lagae,et al.  A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. , 2013, American journal of human genetics.

[16]  N. Boddaert,et al.  Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations , 2014, Human Genetics.

[17]  Steven J. M. Jones,et al.  FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project. , 2014, American journal of human genetics.

[18]  Y. Lacassie,et al.  Unexpected exome sequencing result: De novo TRPS1 mutation in an infant with infantile scoliosis, mild developmental delay, and history of consanguinity , 2014, American journal of medical genetics. Part A.

[19]  R. Greenlee,et al.  Acute health events in adult patients with genetic disorders: The Marshfield Epidemiologic Study Area , 2006, Genetics in Medicine.

[20]  Siddharth Srivastava,et al.  Clinical whole exome sequencing in child neurology practice , 2014, Annals of neurology.

[21]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[22]  Eric Vilain,et al.  Assessing the necessity of confirmatory testing for exome sequencing results in a clinical molecular diagnostic laboratory , 2014, Genetics in Medicine.

[23]  Kim D. Pruitt,et al.  18. The Reference Sequence (RefSeq) Project , 2007 .

[24]  M. Simpson,et al.  De novo mutations in MLL cause Wiedemann-Steiner syndrome. , 2012, American journal of human genetics.

[25]  Kai Ye,et al.  Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads , 2009, Bioinform..

[26]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[27]  Magalie S Leduc,et al.  Clinical whole-exome sequencing for the diagnosis of mendelian disorders. , 2013, The New England journal of medicine.

[28]  Jonathan A. Bernstein,et al.  Clinical whole-exome sequencing: are we there yet? , 2014, Genetics in Medicine.

[29]  Allyn McConkie-Rosell,et al.  The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders , 2013, Genetics in Medicine.

[30]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[31]  Julia Wynn,et al.  The usefulness of whole-exome sequencing in routine clinical practice , 2014, Genetics in Medicine.

[32]  J. Maguire,et al.  Solution Hybrid Selection with Ultra-long Oligonucleotides for Massively Parallel Targeted Sequencing , 2009, Nature Biotechnology.

[33]  P. Stenson,et al.  The Human Gene Mutation Database: 2008 update , 2009, Genome Medicine.

[34]  D. Cooper,et al.  Exome sequencing: Dual role as a discovery and diagnostic tool , 2012, Annals of neurology.