More information about the early utitlity of genetic testing for children with delay. Gratified to be included with these colleagues. - JR
PgmNr 2385: Link to American Society Human Genetics
De novo missense variants in CACNA1A can cause congenital cerebellar ataxia with global developmental delay.Authors:
J.A. Rosenfeld 1 ; T. Harel 1 ; X. Luo 1 ; S. Yamamoto 1 ; M. Hall 2 ; K. Wierenga 2 ; M. Pastore 3 ; D. Bartholomew 3 ; M. Delgado 4 ; Joshua Rotenberg 5 ; R.A. Lewis 1 ; M. Almannai 1 ; L. Emrick 1 ; T. Lotze 1 ; M. Ummat 1 ; C.A. Bacino 1 ; M. Eldomery 1 ; Z. Coban Akdemir 1 ; F. Xia 1 ; H. Bellen 1 ; J. Lupski 1 ; Y. Yang 1 ; B. Lee 1 ; S.R. Lalani 1 ; M. Wangler 1 ; Members of the UDN
1) Molecular & Human Genetics, Baylor College of Medicine, Houston, TX.; 2) University of Oklahoma Health Sciences Center, Oklahoma City, OK; 3) Nationwide Children's Hospital & The Ohio State University, Columbus, OH; 4) Texas Scottish Rite Hospital, Dallas, TX; 5) Houston Specialty Clinic, Houston, TX
Variants in CACNA1A [MIM 601011], encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, are known causes of ataxia: triplet repeat expansions extending a polyglutamine tract in the protein cause adult-onset spinocerebellar ataxia, type 6 [MIM 183086], and heterozygous variants (typically loss-of-function) cause childhood-onset episodic ataxia, type 2 [MIM 108500]. Additionally, missense variants in the gene cause autosomal dominant familial hemiplegic migraines [MIM 141500].
We report five individuals with congenital, non-fluctuating ataxia, hypotonia, ophthalmologic abnormalities, and global developmental delay. Four individuals had a recurrent, de novo c.4991G>A/p.R1664Q variant, which has been described previously in another individual with early-onset, persistent limb and trunk ataxia. The fifth individual has a de novo missense variant, c.5018G>C/p.R1673P. Both missense variants alter arginine residues within the fourth transmembrane domain, changing the pattern of positive charges within the voltage sensor. This pattern is also altered by other severe pathogenic alleles, suggesting that more severe clinical phenotypes could result from disruption of this specific domain. A sixth individual with a severe presentation of neonatal stroke and subsequent refractory epilepsy had a de novo variant within this transmembrane domain, c.5075T>A/p.L1692Q.
To explore the functional consequences of these variants, we generated a loss-of-function (LOF) allele in the homologous gene (cac) in Drosophila that will allow expression of these human variant forms. This LOF allele recapitulates the lethal phenotypes previously observed in cac mutant flies. Human variants will be assessed through their ability to rescue the loss of cac in Drosophila photoreceptors, where conditional knockout causes neurodegeneration, synaptic transmission deficits and neuronal accumulation of autophagic vesicles.
This cohort, combined with previous reports, shows that variants in CACNA1A can cause congenital non-fluctuating cerebellar ataxia and other severe neonatal presentations, thus expanding the spectrum of ataxia and other features associated with this important neuronal calcium channel gene. Functional studies in model organisms will provide further insight into this disease spectrum.