Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family

The very recent discovery of intronic GAAmonoallelic repeat expansions in the FGF14 (fibroblast growth factor 14) gene, as well as the previously described biallelic repeat expansions in the RFC1 (replication factor C subunit 1) gene, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome, have greatly enhanced the diagnostic yield in ataxia, which was previously limited to <50% even with exome sequencing. We describe a Chilean nonconsanguineous family with ataxia from a rural area (Fresia). Seven affected women and five affected men were identified, including 11/20 affected among the offspring in the three younger generations, suggesting high penetrance of an autosomal dominantly inherited cause. Age at onset (AAO) ranged from 17 to 50 years, with seemingly genetic anticipation (Fig. 1A). The index patient is a 29-year-old man who presented with cramps and leg pain at 21 years of age. He progressively developed vertigo, clumsiness, and gait ataxia. He had a history of rapid eye movement sleep behavior disorder (RBD), constipation, and depressive symptoms. His physical examination showed dysarthria, gait and limb ataxia, and absence of deep tendon reflexes. Oculomotor abnormalities or pyramidal features were absent. A sensorimotor chronic moderateto-severe polyneuropathy was diagnosed by nerve conduction studies, and superior vermis brain atrophy was seen on magnetic resonance imaging. All affected family members shared this phenotype (Video S1), with additional features in his grandmother, ie, orolingual dyskinesias, choreoathetosis, and dementia. Genetic testing for ATXN1/2/3/7, CACNA1A, TBP, ATN1, FXN, HTT, and exome sequencing was negative. FGF14 testing demonstrated an expanded allele ( 325 repeats) in three of the four affected and in one unaffected (aged 62 years) family member (Fig. 1A,B). Incomplete segregation could not be explained by a sample mix-up as relationship and sex were tested by nine polymorphic microsatellite markers, including two markers each on the X and Y chromosomes. Notably, repeat-primed PCR suggested repeat interruption in all four tested FGF14 expansion carriers in the Chilean family (Figure 1C). Due to vertigo in one affected, we also tested for RFC1 expansions in all available family members revealing a biallelic repeat expansion in one unaffected family member, aged 18 years, ie, well younger than the average AAO of RFC1 patients (Fig. 1A,C). This is the first Latin American family in whom an expanded FGF14 repeat was found. Although the definitive range for normal vs. intermediate/reduced penetrance vs. pathogenic/full penetrance alleles has not yet been determined, 250 and 300 repeats have been suggested as the respective boundaries. Importantly, however, the GAA repeat in our family is interrupted, and only pure expanded alleles have currently been identified in affected individuals. The phenotype in this family with the interrupted FGF14 repeat expansion of uncertain clinical relevance differs from the two series published to date, as ocular abnormalities were absent and additional features were consistently observed, such as polyneuropathy, RBD, constipation, and depression. Notably, there is co-occurrence of an only heterozygous RFC1 repeat expansion in at least one affected and one unaffected family member with an additional heterozygous expansion in FGF14 (Fig. 1A). However, at this stage, it is unclear whether there is an additive effect of expanded repeats in both genes. Interestingly, patient L14997 appears to be the most severely affected in this family. Since the role of the interrupted FGF14 repeat expansion could not be determined unambiguously in this family, another, as yet unidentified genetic variant/repeat expansion could contribute to the disease. Furthermore, it is important to not only determine the length of the FGF14 repeat but also its architecture in unexplained spinocerebellar ataxia.