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Eur J Hum Genet. 2019 Mar;27(3):408-421. doi: 10.1038/s41431-018-0299-8. Epub 2018 Dec 14.

The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study.

Author information

1
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, 8952, Switzerland.
2
Victor Babes National Institute of Pathology, Bucharest, 050096, Romania.
3
Division of Child Neurology, University Children's Hospital Zurich, Zurich, 8032, Switzerland.
4
CRC Clinical Research Center University, Children's Hospital Zurich, Zurich, 8032, Switzerland.
5
radiz-Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases University of Zurich, Zurich, 8032, Switzerland.
6
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, 91054, Germany.
7
Pediatric Emergency Department, University Children's Hospital Zurich, Zurich, 8032, Switzerland.
8
Children's department, Swiss Epilepsy Centre, Clinic Lengg, Zurich, 8000, Switzerland.
9
Division of Child Neurology, Kantonsspital Winterthur, Winterthur, 8401, Switzerland.
10
Municipal Hospital of Zurich Triemli, Zurich, 8063, Switzerland.
11
Division of Child Neurology, Children's Hospital, Lucerne, 6000, Switzerland.
12
Department of Woman-Mother-Child, University Medical Center CHUV, Lausanne, 1015, Switzerland.
13
Division of Paediatric Neurology, University Childerns Hospital Basel, UKBB, 4031, Basel, Switzerland.
14
Division of Paediatric Neurology, Development and Rehabilitation, University Children's Hospital, 3010, Bern, Switzerland.
15
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, 8057, Switzerland.
16
Division of General Pediatrics, Department of Pediatrics, Medical University of Graz, 8036, Graz, Austria.
17
Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, 8952, Switzerland. anita.rauch@medgen.uzh.ch.
18
radiz-Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases University of Zurich, Zurich, 8032, Switzerland. anita.rauch@medgen.uzh.ch.
19
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, 8057, Switzerland. anita.rauch@medgen.uzh.ch.
20
Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, 8057, Switzerland. anita.rauch@medgen.uzh.ch.

Abstract

Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.

PMID:
30552426
DOI:
10.1038/s41431-018-0299-8

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