Frequencies of Mutations in 20 Genes Associated with Hereditary Ataxia: Experience from a US Clinical Laboratory (P2.135)

OBJECTIVE: To assess the mutation frequencies in 20 genes associated with hereditary ataxia in 2,165 specimens referred to a US clinical laboratory for genetic testing. BACKGROUND: The European Federation of Neurological Societies (EFNS) recommends testing for prevalent ataxias including autosomal dominant (AD) SCA1, 2, 3, 6, 7 and 17, and autosomal recessive (AR) Friedreich ataxia (FRDA). SCA8 is not usually recommended for initial testing because of its complex inheritance pattern and incomplete penetrance. DESIGN/METHODS: A total of 2,165 patients were tested for mutations in: DRPLA ( ATN1 ), SCA1 ( ATXN1 ), SCA2 ( ATXN2), SCA3 ( ATXN3 ), SCA6 ( CACNA1A ), SCA7 ( ATXN7 ), SCA8 ( ATXN8OS ), SCA10 ( ATXN10 ), SCA12 ( PPP2R2B ), SCA17 ( TBP ), SCA5 ( SPTBN2 ), SCA14 ( PRKCG ), SCA28 ( AFG3L2 ), and SCA13 ( KCNC3 ); and 6 AR genes: FRDA ( FXN) , POLG , APTX , SETX , SIL1, and TTPA . Repeat expansions were analyzed by PCR, repeat-primed PCR, and Southern blot assay. Base-pair mutations were assessed by Sanger sequencing. RESULTS: Positive results for one or more genes were identified in 254 (11.7[percnt]) patients; 204 (80.3[percnt]) in AD genes and 50 (19.7[percnt]) in AR genes. The majority (92.9[percnt]) had repeat expansions, as compared to 7.1[percnt] with pathogenic sequence variants. SCA1, 2, 3, 6, 7, and 17 accounted for 56.3[percnt] of the total positive results, while FRDA accounted for 15.7[percnt]. Repeat expansion disorder frequencies were: SCA1 (6.7[percnt]), SCA2 (13.8[percnt]), SCA3 (16.1[percnt]), SCA6 (16.1[percnt]), SCA7 (1.6[percnt]), SCA8 (18.1[percnt]), SCA10 (2.4[percnt]), SCA12 (0.4[percnt]), SCA17 (2.0[percnt]), DRPLA (none), and FRDA (15.7[percnt]). There were 480 variants of unknown significance detected in this study. CONCLUSIONS: Our data concurs with the EFNS recommendations for initial genetic testing except for the exclusion of SCA10. The higher frequency of SCA10 (2.4[percnt]) may be due to population differences. An evaluation of less common ataxia genes and those with incomplete penetrance (SCA8) may be considered after initial testing for prevalent genetic causes. Study Supported by: Quest Diagnostics Disclosure: Dr. Wang has received personal compensation for activities with Quest Diagnostics. Dr. Meservey has received personal compensation for activities with Quest Diagnostics. Dr. McCarthy has received personal compensation for activities with Quest Diagnostics. Dr. Batish has received personal compensation for activities with Quest Diagnostics. Dr. Jaremko has received personal compensation for activities with Quest Diagnostics. Dr. Suer has received personal compensation for activities with Quest Diagnostics. Dr. Higgins has received personal compensation for activities with Quest Diagnostics.