Biallelic <scp><i>CACNA1A</i></scp> variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen, Vivien; Kolesnik-Taylor, Anna; Eck, Josefine; Sabanathan, Saras; Spasić-Bošković, Olivera; Maw, Anna; Baker, Kate

doi:10.1002/ajmg.a.62960

Cited by 7 publications

(1 citation statement)

References 28 publications

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“…HMOX2 is a constitutive gene that plays a role in heme catabolism, leading to antioxidant and anti-inflammatory effects [117]. CACNA1A encodes the alpha-1a subunit of the voltage-dependent P/Q calcium channel, and has been linked repeatedly to familial hemiplegic migraine (FHM), a subtype of MA [118]. Finally, MPPED2 is a metallophosphoesterase domain-containing protein which has been linked to various functions, including tumor suppression [119].…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

Zalaquett,

Salameh,

Kim

et al. 2024

JCM

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Background: Migraine is a prevalent episodic brain disorder known for recurrent attacks of unilateral headaches, accompanied by complaints of photophobia, phonophobia, nausea, and vomiting. Two main categories of migraine are migraine with aura (MA) and migraine without aura (MO). Main body: Early twin and population studies have shown a genetic basis for these disorders, and efforts have been invested since to discern the genes involved. Many techniques, including candidate-gene association studies, loci linkage studies, genome-wide association, and transcription studies, have been used for this goal. As a result, several genes were pinned with concurrent and conflicting data among studies. It is important to understand the evolution of techniques and their findings. Conclusions: This review provides a chronological understanding of the different techniques used from the dawn of migraine genetic investigations and the genes linked with the migraine subtypes.

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Section: Genome-wide Association Studiesmentioning

confidence: 99%

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

Zalaquett,

Salameh,

Kim

et al. 2024

JCM

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Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen

Kolesnik-Taylor

Eck

et al. 2022

American J of Med Genetics Pt A

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Biallelic variants in CACNA1A have previously been reported in nine individuals (four families) presenting with epilepsy and cognitive impairments of variable severity and age-of-onset. Here, we describe a child who presented at 6 months of age with drugresistant epilepsy and developmental delay. At 10 years of age, she has profound impairments in motor function and communication. MRI was initially unremarkable, but progressed to severe cerebellar atrophy by age 3 years. Next Generation Sequencing and panel analysis identified a maternally inherited truncating variant c.2042_2043delAG, p.(Gln681ArgfsTer100) and paternally inherited missense variant c.1693G>A, p.(Glu565Lys). In contrast to previously reported biallelic cases, parents carrying these monoallelic variants did not display clear signs of a CACNA1Aassociated syndrome. In conclusion, we provide further evidence that biallelic CAC-NA1A variants can cause a severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities of genetic counseling in such situations.

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Exome sequencing in Nigerian children with early‐onset epilepsy syndromes

Ademuwagun,

Adam,

Rotimi

et al. 2024

Epilepsia Open

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ObjectiveNigeria, along with other Sub‐Saharan African countries, bears the highest burden of epilepsy worldwide. This high prevalence is attributed to a combination of factors, including a significant incidence of infectious diseases, perinatal complications, and genetic etiologies. Genetic testing is rarely available and is not typically included in the routine diagnostic work‐up for individuals with infantile and childhood epilepsy syndromes in these regions. Exome sequencing (ES) offers a diagnostic yield of 24%–62%, but these figures primarily reflect data from high‐income countries (HICs) and may not be applicable to low‐ and middle‐income countries (LMICs). In this study, we employed ES to investigate the genetic basis of early‐onset epilepsy in 22 affected children from Nigeria.MethodsThe study involved sampling of patients diagnosed with early‐onset epilepsy syndromes at the Lagos State University Teaching Hospital (LASUTH) Neurology clinic. Venous blood samples were collected, and genomic DNA was isolated and purified. Molecular analysis included DNA fragmentation, ligation, target enrichment, library preparation, and whole‐exome sequencing. Computational analysis involved variant calling, curation, and classification using specialized tools and databases.ResultsPathogenic variants were identified in 6 out of 22 individuals, equaling a diagnostic yield of 27.3% and comprising variants in BPTF, NAA15, SCN1A, TUBA1A and twice in CACNA1A.SignificanceIn this study, we present the first exome study on early‐onset epilepsy syndromes from West Africa, facilitated by a Nigerian‐German research collaboration. Our findings reveal a genetic diagnostic yield comparable to that of HICs. The integration of genomic medicine into epilepsy management in Nigeria holds promising prospects for improving patient care and reducing mortality rates.Plain Language SummaryThis study represents the first published exome findings in Nigerian children with early‐onset epilepsy, revealing a genetic diagnosis in 27% of cases. Pathogenic variants were identified in five genes amongst 6 of 22 patients, underscoring the potential of genetic testing to enhance epilepsy management in developing nations like Nigeria.

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Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Cited by 7 publications

References 28 publications

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Exome sequencing in Nigerian children with early‐onset epilepsy syndromes

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