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Original Investigation
March 2017

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Author Affiliations
  • 1Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • 2Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany
  • 3Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  • 4National Research Center, Dokki, Cairo, Egypt
  • 5Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan
  • 6Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
  • 7Institute of Human Genetics, Technische Universität München, Munich, Germany
  • 8Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany
  • 9private practice, Jdaidet Artouz, Jdaidet Artouz, Syria
  • 10private practice, Sanameen, Sanameen, Syria
  • 11Hamad Medical Corporation, Qatar
  • 12private practice, Shahbaa, Shahbaa, Syria
  • 13private practice, Kraya, Kraya, Syria
  • 14private practice, Jesser El Sheghour, Syria
  • 15private practice, Lattakia, Lattakia, Syria
  • 16Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
  • 17Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
  • 18Institute of Human Genetics, University Duisburg-Essen, Essen, Germany
  • 19Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany
JAMA Psychiatry. 2017;74(3):293-299. doi:10.1001/jamapsychiatry.2016.3798
Key Points

Question  How can the heterogeneous genetic causes of autosomal recessive neurodevelopmental disorders be identified?

Findings  Clinical examination was performed on 152 consanguineous families with affected children. Using exome sequencing, the causative genetic variant was clarified in 36.8% of the families, and 52 convincing candidate genes were identified.

Meaning  Exome sequencing is recommended as first-line routine genetic testing in individuals with intellectual disability, with this approach validating several candidate genes and enriching the literature with further candidates; identifying relevant mechanisms is essential to understand its pathogenesis and develop therapies.


Importance  Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown.

Objectives  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.

Design, Setting, and Participants  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.

Results  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%]).

Conclusions and Relevance  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.