Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability

Overview

Journal Arch Iran Med

Specialty General Medicine

Date 2023 Aug 6

PMID 37543906

Authors

Naeim Ehtesham

Meysam Mosallaei

Maryam Beheshtian

Shahrouz Khoshbakht

Mahsa Fadaee

Raheleh Vazehan

Mehrshid Faraji Zonooz

Parvaneh Karimzadeh

Kimia Kahrizi

Hossein Najmabadi

Affiliations

Soon will be listed here.

Abstract

Background: Ion channel dysfunction in the brain can lead to impairment of neuronal membranes and generate several neurological diseases, especially neurodevelopmental disorders.

Methods: In this study, we set out to delineate the genotype and phenotype spectrums of 14 Iranian patients from 7 families with intellectual disability (ID) and/or developmental delay (DD) in whom genetic mutations were identified by next-generation sequencing (NGS) in 7 channel-encoding genes: and . Moreover, the data of 340 previously fully reported ID and/or DD cases with a mutation in any of these seven genes were combined with our patients to clarify the genotype and phenotype spectrum in this group.

Results: In total, the most common phenotypes in 354 cases with ID/DD in whom mutation in any of these 7 channel-encoding genes was identified were as follows: ID (77.4%), seizure (69.8%), DD (59.8%), behavioral abnormality (29.9%), hypotonia (21.7%), speech disorder (21.5%), gait disturbance (20.9%), and ataxia (20.3%). Electroencephalography abnormality (33.9%) was the major brain imaging abnormality.

Conclusion: The results of this study broaden the molecular spectrum of channel pathogenic variants associated with different clinical presentations in individuals with ID and/or DD.

Citing Articles

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation.

Cipriano L, Piscopo R, Aiello C, Novelli A, Iolascon A, Piscopo C Children (Basel). 2024; 11(5).

PMID: 38790536 PMC: 11119747. DOI: 10.3390/children11050541.

References

Trudeau M, Dalton J, Day J, Ranum L, Meisler M . Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2005; 43(6):527-30. PMC: 2564538. DOI: 10.1136/jmg.2005.035667. View

Ogden K, Chen W, Swanger S, McDaniel M, Fan L, Hu C . Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology. PLoS Genet. 2017; 13(1):e1006536. PMC: 5240934. DOI: 10.1371/journal.pgen.1006536. View

Yarotskyy V, Gao G, Peterson B, Elmslie K . The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol. 2008; 587(3):551-65. PMC: 2670080. DOI: 10.1113/jphysiol.2008.161737. View

Wagnon J, Meisler M . Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. Front Neurol. 2015; 6:104. PMC: 4432670. DOI: 10.3389/fneur.2015.00104. View

Spillane J, Kullmann D, Hanna M . Genetic neurological channelopathies: molecular genetics and clinical phenotypes. J Neurol Neurosurg Psychiatry. 2015; 87(1):37-48. PMC: 4717447. DOI: 10.1136/jnnp-2015-311233. View

Swanger S, Chen W, Wells G, Burger P, Tankovic A, Bhattacharya S . Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. Am J Hum Genet. 2016; 99(6):1261-1280. PMC: 5142120. DOI: 10.1016/j.ajhg.2016.10.002. View

Al Dhaibani M, El-Hattab A, Holroyd K, Orthmann-Murphy J, Larson V, Siddiqui K . Novel mutation in the KCNJ10 gene in three siblings with seizures, ataxia and no electrolyte abnormalities. J Neurogenet. 2017; 32(1):1-5. DOI: 10.1080/01677063.2017.1404057. View

Coutelier M, Blesneac I, Monteil A, Monin M, Ando K, Mundwiller E . A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Am J Hum Genet. 2015; 97(5):726-37. PMC: 4667105. DOI: 10.1016/j.ajhg.2015.09.007. View

Burnashev N, Szepetowski P . NMDA receptor subunit mutations in neurodevelopmental disorders. Curr Opin Pharmacol. 2014; 20:73-82. DOI: 10.1016/j.coph.2014.11.008. View

10.

Kessi M, Chen B, Peng J, Yan F, Yang L, Yin F . Calcium channelopathies and intellectual disability: a systematic review. Orphanet J Rare Dis. 2021; 16(1):219. PMC: 8120735. DOI: 10.1186/s13023-021-01850-0. View

11.

Barresi S, Dentici M, Manzoni F, Bellacchio E, Agolini E, Pizzi S . Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations. Pediatr Neurol. 2019; 104:40-45. DOI: 10.1016/j.pediatrneurol.2019.09.005. View

12.

Trinh J, Kandaswamy K, Werber M, Weiss M, Oprea G, Kishore S . Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders. J Neurodev Disord. 2019; 11(1):11. PMC: 6593513. DOI: 10.1186/s11689-019-9270-4. View

13.

Kosaki R, Ono H, Terashima H, Kosaki K . Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval. Am J Med Genet A. 2018; 176(7):1657-1661. DOI: 10.1002/ajmg.a.38833. View

14.

Celmina M, Micule I, Inashkina I, Audere M, Kuske S, Pereca J . EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients. Clin Genet. 2018; 95(1):63-78. DOI: 10.1111/cge.13374. View

15.

Hu C, Chen W, Myers S, Yuan H, Traynelis S . Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci. 2016; 132(2):115-121. PMC: 5125235. DOI: 10.1016/j.jphs.2016.10.002. View

16.

Hermida A, Jedraszak G, Kubala M, Mathiron A, Berna P, Bennis Y . Long-term follow-up of a patient with type 2 Timothy syndrome and the partial efficacy of mexiletine. Gene. 2021; 777:145465. DOI: 10.1016/j.gene.2021.145465. View

17.

Noebels J . Precision physiology and rescue of brain ion channel disorders. J Gen Physiol. 2017; 149(5):533-546. PMC: 5412535. DOI: 10.1085/jgp.201711759. View

18.

Vinksel M, Writzl K, Maver A, Peterlin B . Improving diagnostics of rare genetic diseases with NGS approaches. J Community Genet. 2021; 12(2):247-256. PMC: 8141085. DOI: 10.1007/s12687-020-00500-5. View

19.

Wagnon J, Barker B, Ottolini M, Park Y, Volkheimer A, Valdez P . Loss-of-function variants of in intellectual disability without seizures. Neurol Genet. 2017; 3(4):e170. PMC: 5499976. DOI: 10.1212/NXG.0000000000000170. View

20.

Soldovieri M, Miceli F, Taglialatela M . Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. Physiology (Bethesda). 2011; 26(5):365-76. DOI: 10.1152/physiol.00009.2011. View