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Advanced Neurology ADGRV1 and MED13L mutation

Table 1. Whole‑exome sequencing report of the proband
Gene (Transcript) Location Variant Zygosity Disease (OMIM) Inheritance Classification
ADGRV1 (+) Exon 7 c. 1169dup Heterozygous Familial febrile seizures-4 Autosomal Likely pathogenic
(ENST00000405460.9) (p.Tyr390Ter) (OMIM#604352) dominant (PVS1, PM2)
MED13L (−) Exon 10 c. 1333_1339del Heterozygous Impaired intellectual Autosomal Likely pathogenic
(ENST00000281928.9) (p.Ser445GlnfsTer38) development and distinctive dominant (PVS1, PM2)
facial features with or without
cardiac defects
(OMIM#616789)
Abbreviations: ADGRV1: Adhesion G protein-coupled receptor V1; MED13L: Mediator complex subunit 13-like; OMIM: Online Mendelian
Inheritance in Man; PM: Moderate evidence of pathogenicity; PVS: Very strong evidence of pathogenicity.

Table 2. Sanger sequencing of the child and parents
Gene and Variant Location Allele state Inheritance Disorder Classification Inherited
transcript form
MED13L c. 1333_1339d Exon 10 Chr12:116009074 Heterozygous Autosomal Impaired intellectual Likely De novo
NM_015335.5 eITCTCAAC dominant development and pathogenic
(p.Ser445GInfs*38) distinctive facial
features with or
without cardiac defects
(OMIM#616789
ADGRV1 c. 1169dupA Exon 7 Heterozygous Autosomal Familial febrile Uncertain Unaffected
NM_032119.4 (p.Tyr390Ter) Chr5:90627707 dominant seizures-4 significance mother
(OMIM#604352)
Abbreviations: ADGRV1: Adhesion G protein-coupled receptor V1; MED13L: Mediator complex subunit 13-like; OMIM: Online Mendelian
Inheritance in Man.

seizures. Reported cases had febrile seizures, late onset to precisely describe the phenotypic spectrum associated
infantile spasms, and Lennoux–Gastaut syndrome. The with ADGRV1 variants, a review of the literature suggests
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variant detected in our patient is novel, and to the best of that seizures in these phenotypes are mostly self-limiting
our knowledge, this is the first case of a frameshift mutation or can be controlled with monotherapy. The phenotype of
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in MED13L presenting with refractory epilepsy. Unlike this gene does not exactly match with that of our patient as
non-silent mutations, which mostly include missense and she has refractory epilepsy with facial dysmorphism and
nonsense mutations, frameshift mutation, as observed in development delay.
this case, is considered the most damaging mutation. It
leads to significant DNA damage as it completely changes Regarding ADGRV1, the extracellular domain of
the reading frame in the process of protein synthesis. VLGR1b contains 35 CalX-β motifs, which resemble
+
2+
Addressing the other mutated gene in our patient, the regulatory domains of Na /Ca exchangers. In the
+
2+
ADGRV1, the loss-of-function mutation in this gene central nervous system, Na –Ca exchanges play a
results in Usher syndrome characterized by sensorineural fundamental role in controlling changes in the intracellular
2+
+
hearing deficiencies at birth and subsequent development concentrations of Na and Ca ions that occur in
of progressive retinitis pigmentosa. Variants in ADGRV1 physiologic conditions, such as neurotransmitter release,
have been associated with epilepsy. In a recent study of cell migration and differentiation, and gene expression,
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101 cases with febrile seizures and epilepsy with antecedent as well as neurodegenerative processes. Therefore, the
febrile seizures, ADGRV1 variants were identified in nine disruption in function caused by variants in the CalX-β
unrelated cases, indicating that it is a susceptibility gene. motif is potentially involved with epileptogenesis.
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Missense variants of the gene have been linked to genetic Although the MED13L subunits relay information from
generalized epilepsy and myoclonic epilepsies, with a temporal/spatial signals or transcription factors to the RNA
7
5
recent study showing that biallelic variants are associated polymerase II machinery, thereby controlling the expression
with Rolandic epilepsy. In most of these cases, the of specific genes required for the neurodevelopment, the
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4,6
variants were inherited from asymptomatic parents, exact molecular mechanisms behind epileptogenesis remains
as observed in our case, which may be explained by unknown. The expression or activity of one gene can influence
incomplete penetrance. Although further study is needed the expression or activity of another gene, often in a regulatory
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Volume 4 Issue 1 (2025) 113 doi: 10.36922/an.3602