An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14.

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

KBG syndrome presenting with brachydactyly type E.

We report the case of a young woman who presented at age 10 years with height on the tenth centile, brachydactyly type E and mild developmental delay. Biochemistry and hormonal profiles were normal. Differential diagnoses considered included Albright hereditary osteodystrophy without hormone resistance (a.k.a pseudopseudohypoparathyroidism), 2q37 microdeletion syndrome and acrodysostosis. She had a normal karyotype and normal FISH of 2q37. Whole genome sequencing (WGS) identified a mutation in the ANKRD11 gene associated with KBG syndrome. We review the clinical features of the genetic syndromes considered, and suggest KBG syndrome be considered in patients presenting with syndromic brachydactyly type E, especially if short stature and developmental delay are also present.