Objective: To present case series of four patients of heterozygous for SYNE1 mutation with phenotype consistent with cerebellar ataxia.

Background: Recessive cerebellar ataxias are defined as disorders with autosomal recessive inheritance characterized by a cerebellar motor syndrome of gait ataxia, dysmetria, adiadochokinesia, nystagmus, and dysarthria associated with cerebellar degeneration as demonstrated by imaging or pathology with pathogenic mutation. There are currently over fifty primary recessive ataxias, and none of the recessive ataxias has pure cerebellar phenotype. Until recently the prototype of the relatively pure, slowly progressive cerebellar ataxia was SYNE1-related autosomal recessive cerebellar ataxia 1. Recently more and more cases with additional phenotypes has been reported in patients with homozygous SYNE1 and compound heterozygous SYNE1 mutations.

Method: We describe genotypic variations and phenotypic findings in a cohort of 4 ataxia patients, presented to the Department of Neurology of the University of Florida, who tested positive for SYNE1 mutation.

Results: We report 4 heterozygous patients, who presented with a phenotype of cerebellar ataxia. Case 1 was heterozygous for SACS (c 13717A>C; p.Asn4573His), SYNE1 (c.23315 G>A; p Arg7772Gln), and POLG (c.660-9C>T). Case 2 had a Heterozygous Missense mutation in SYNE1 (c.14018G>A; p.Arg4673Gln), case 3 had a heterozygous missense mutation for autosomal dominantly inherited ataxia SCA-6 (CACNA1), and also had a heterozygous missense mutation in SYNE1 (c.3188T>C; p.Val1063Ala), ANO10 (AR carrier). Case 4 was found to have heterozygous missense mutation in SYNE1 (c.578G>A; p.Gly193Asp).

Conclusion: All four cases we presented exhibited ataxia phenotype, despite being heterozygous for autosomal recessive gene SYNE1. Half of the cases had additional mutations either significant or of indeterminate significance for ataxia phenotype. Further genetic testing, such as obtaining a full ataxia panel, is recommended for the patients who are heterozygous for autosomal recessive ataxias and has a known causative gene mutation. Additional testing may help identify additional mutations which contributed to the phenotype.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unravelling-hidden-mutations-behind-the-heterozygos-syne1-genotype/