Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.
European Journal of Medical Genetics. 2019-06-01; 62(6): 103530
DOI: 10.1016/j.ejmg.2018.08.011
Read on PubMed
1. Eur J Med Genet. 2019 Jun;62(6):103530. doi: 10.1016/j.ejmg.2018.08.011. Epub
2018 Aug 22.
Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a
CACNA1A pathogenic variant.
Angelini C(1), Van Gils J(2), Bigourdan A(3), Jouk PS(4), Lacombe D(2), Menegon
P(3), Moutton S(5), Riant F(6), Sole G(7), Tournier-Lasserve E(6), Trimouille
A(2), Vincent M(8), Goizet C(9).
Author information:
(1)Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM
U1211, Univ. Bordeaux, Bordeaux, France. Electronic address:
.
(2)Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM
U1211, Univ. Bordeaux, Bordeaux, France.
(3)Service de Neuroradiologie, CHU de Bordeaux, France.
(4)Service de Génétique Médicale, CHU de Grenoble, France.
(5)Service de Génétique Médicale, CHU de Dijon, France.
(6)Service de Génétique Moléculaire, Hôpital Lariboisière, Paris, France.
(7)Service de Neurologie Médicale, CHU de Bordeaux, France.
(8)Service de Génétique Médicale, CHU de Nantes, France.
(9)Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM
U1211, Univ. Bordeaux, Bordeaux, France; Centre de Référence Neurogénétique,
Service de Génétique Médicale, CHU de Bordeaux, France.
The CACNA1A gene encodes a calcium-dependent voltage channel, localized in
neuronal cells. Pathogenic variants in this gene are known to lead to a broad
clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type
6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We
report a large family revealing a wide variability of neurological manifestations
associated with a CACNA1A missense pathogenic variant. The index case had
early-onset epileptic encephalopathy with progressive cerebellar atrophy,
although his mother and his great-grandmother suffered from paroxystic episodic
ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her
sons displayed early-onset ataxia with intellectual disability. Two of her little
daughters suffered from gait disorders, and also from epilepsy for one of them.
All these relatives were carriers of the previously described heterozygous
variant in CACNA1A gene. We report here the first family leading to major
clinical variability and incomplete penetrance. Our family highlights the
difficulties to provide accurate genetic counselling concerning prenatal
diagnosis regarding highly variable severity of the clinical presentation.
Copyright © 2018 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmg.2018.08.011
PMID: 30142438 [Indexed for MEDLINE]