title: Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
abstract: Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown.
  
  
  
  To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families.
  
  
  
  Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016.
  
  
  
  Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]).
  
  
  
  Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany2Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Tawamie
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany3Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: National Research Center, Dokki, Cairo, Egypt.
authors.forename: Ola
authors.initials: O
authors.lastname: Hosny Gebril
authors.affiliation: Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan.
authors.forename: Tawfiq
authors.initials: T
authors.lastname: Froukh
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Krumbiegel
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoyer
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Eberlein
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Scheller
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany7Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.affiliation: National Research Center, Dokki, Cairo, Egypt.
authors.forename: Ehab R
authors.initials: ER
authors.lastname: Abdelraouf
authors.affiliation: National Research Center, Dokki, Cairo, Egypt.
authors.forename: Nagwa A
authors.initials: NA
authors.lastname: Meguid
authors.affiliation: private practice, Jdaidet Artouz, Jdaidet Artouz, Syria.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Abboud
authors.affiliation: private practice, Sanameen, Sanameen, Syria11Hamad Medical Corporation, Qatar.
authors.forename: Mohammed Ayman
authors.initials: MA
authors.lastname: Al Khateeb
authors.affiliation: private practice, Shahbaa, Shahbaa, Syria.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Fakher
authors.affiliation: private practice, Kraya, Kraya, Syria.
authors.forename: Saber
authors.initials: S
authors.lastname: Hamdan
authors.affiliation: private practice, Jesser El Sheghour, Syria.
authors.forename: Amina
authors.initials: A
authors.lastname: Ismael
authors.affiliation: private practice, Lattakia, Lattakia, Syria.
authors.forename: Safia
authors.initials: S
authors.lastname: Muhammad
authors.affiliation: Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
authors.forename: Ebtessam
authors.initials: E
authors.lastname: Abdallah
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Institute of Human Genetics, University Duisburg-Essen, Essen, Germany19Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany2Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D002648:Child; D002869:Chromosome Aberrations; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005858:Germany; D006720:Homozygote; D006801:Humans; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D017422:Sequence Analysis, DNA