Authors :
First Author: Dana Kuwait University, MD, MSc – Kuwait University
Presenting Author: mona Alenzi, MD – University of toronto
Mona Alenzi, MD – Kuwait Ministry of Health; Khalid Haraz, MD – Pediatrics – Adan Hospital, Ministry of Health, Kuwait; Ehab El-Anany, MD – Pediatrics – Adan Hospital, Ministry of Health, Kuwait; Mohamed Zakkariah, MD – Pediatrics – Adan Hospital, Ministry of Health, Kuwait
Rationale: The Middle Eastern population is characterized by large family size and high rate of consanguinity, with first-cousin marriages being the most common. The prevalence of consanguinity in Kuwait is 50% and approaches 90% in some rural areas. Therefore, autosomal recessive disease traits constitute the overwhelming percentage of genetic disorders.
Because many cases with neurodevelopmental disorders and epilepsies remain undiagnosed despite extensive clinical investigations, we founded the first neurogenetic clinic in Kuwait at the Adan hospital in February 2021 to facilitate genetic testing for the undiagnosed families, provide family-based counseling, and offer precise interventions when available.
Methods: We performed a retrospective chart review of all families presenting to Adan Hospital neurogenetic clinic in Kuwait between February 2021 to June 2023. We particularly focused on our analysis of families with epilepsy (FWE) and/or developmental epileptic encephalopathy (DEE).
Results: A total of 126 families with different neurodevelopmental disorders and epilepsies were evaluated; majority (77%) of the families (97/126) were singleton while 23% (29/126) were multiplex with two to four children affected. Referring services include general pediatrics clinics (59% families), child neurology clinics (26% families), self-referral (7% families), genetics clinics (6% families), and developmental clinic or orthopedics clinic (1% of families each).
Epilepsy was a main presenting feature in 40% (50/126 families). Of those, 19 families (38%) presented with DEE. A molecular etiology was identified in 56% (28/50) of FWE. Novel variants in a known gene accounted for the majority (78%) of diagnosed FEW, followed by a known pathogenic variant in a known gene in 18% (5/28 FWE) and a potential novel disease gene under research investigation in 10% (3/28 FWE). Interestingly, founder variants accounted for 21% of the molecularly-diagnosed FWE while 79% were due private variants. The mode of inheritance was autosomal recessive in 75% (21/28 FWE) followed by autosomal dominant (due to
de novo variants) in 21% (6/28 FWE), and X-linked recessive in only 3% (1/28 FWE).
Subsequently, the genetic result informed the diagnosis and family-based counseling in all molecularly-diagnosed FWE with 17 young couple of the 28 FWE (61%) being referred for preimplantation genetic testing or prenatal diagnosis for future pregnancies. A precise intervention was/is being implemented in 14% (4/28 FWE) such as use of Migalastat to halt progress of
SCARB2 -related progressive myoclonic epilepsy type 4, use of ganoxolone for CDKL5-related epilepsy, use of sodium channel blockers in SCN2A-related DEE, or referral for bone marrow transplant for
ABCD4-related X-linked adrenoleukodystrophy.
Conclusions: Our study demonstrates the unique opportunities offered by reaching molecular etiology in FWE and DEE from consanguineous populations. Studying diverse population can aid in identifying novel variants in known epilepsy disease genes as well as potential novel genes, can direct family-based counseling, and allows for precise management and intervention.
Funding: No funding was recieved for this project.