Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders
Authors: Miriam S. Reuter, Hasan Tawamie, Rebecca Buchert, Ola Hosny Gebril, Tawfiq Froukh, Christian Thiel, Steffen Uebe, Arif B. Ekici, Mandy Krumbiegel, Christiane Zweier, Juliane Hoyer, Karolin Eberlein, Judith Bauer, Ute Scheller, Tim M. Strom, Sabine Hoffjan, Ehab R. Abdelraouf, Nagwa A. Meguid, Ahmad Abboud, Mohammed Ayman Al Khateeb, Mahmoud Fakher, Saber Hamdan, Amina Ismael, Safia Muhammad, Ebtessam Abdallah, Heinrich Sticht, Dagmar Wieczorek, André Reis, Rami Abou Jamra
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. <h3>Objectives</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Results</h3> 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<i>PAH</i>,<i>CBS</i>,<i>MTHFR</i>,<i>CYP27A1</i>, and<i>HIBCH</i>), 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<i>GRM7</i>,<i>STX1A</i>,<i>CCAR2</i>,<i>EEF1D</i>,<i>GALNT2</i>,<i>SLC44A1</i>,<i>LRRIQ3</i>,<i>AMZ2</i>,<i>CLMN</i>,<i>SEC23IP</i>,<i>INIP</i>,<i>NARG2</i>,<i>FAM234B</i>, and<i>TRAP1</i>. 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%]). <h3>Conclusions and Relevance</h3> 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.