POG02 Variant ataxia telangiectasia in siblings with normal  -fetoprotein levels

Abstract

IntroductionAtaxia telangiectasia (A-T) is a multisystem, degenerative disorder caused by mutation of the A-T mutated (ATM) gene. Classic A-T presents with ataxia and ocular telangiectasia in association with immunodeficiency, increased risk for malignancy, increased serum α-fetoprotein levels, radiosensitivity, and chromosomal instability. Variant A-T presents as a milder phenotype with an extended lifespan and may be due to residual ATM kinase activity. Two siblings with variant AT are described.Case DescriptionThe eldest sister is 24-years-old and became wheelchair bound by age 22, following 20 years of progressive gait ataxia. She has choreo-athetoid movements of the arms and neck. Her younger sister is 20-years-old and presents with writing difficulty. She exhibits focal dystonia and blepharospasm, in addition to ocular telangiectasia. She remains independently mobile.Results of InvestigationsBoth sisters have normal α-fetoprotein levels, with no immunodeficiency or endocrinopathy. Two mutations (c.9022C>T and c.1066-6T>G) were identified. The c.9022 mutation has no ATM kinase activity, but some ATM kinase activity is expressed by the c.1066 mutant allele in cells from these patients.DiscussionThese siblings present with a milder phenotype and extrapyramidal signs, in keeping with recent descriptions of variant A-T. The absence of elevated α-fetoprotein levels should not deter physicians in pursuing this diagnosis.

Evidence of pathogenicity for the leaky splice variant c.1066‐6T>G in ATM

“…In the case presented here, c.1066‐6T>G is located in trans with a known disease‐causing allele, c.2250G>A, in a patient with variant A‐T and no other pathogenic ATM allele detected after exome sequencing. The results of our functional analysis are consistent with observations reported previously in patients with variant forms of A‐T (Dörk et al, 2004; Taylor et al, 2015; van Os et al, 2019) and with previously described patients who were reported with the c.1066‐6T>G variant (Albertyn et al, 2010; Austen et al, 2008). This provides strong evidence for the pathogenicity of the c.1066‐6T>G allele, although the attenuated and partial expression of clinical symptoms is indicative of a reduced penetrance and reduced expressivity of this variant.…”

“…If so, it would be predicted that compound heterozygosity for c.1066‐6T>G and a classic pathogenic ATM variant causes a more severe phenotype than the homozygous state of c.1066‐6T>G. Indeed, c.1066‐6T>G was reported in conjunction with the c.9022C>T (p.Arg3008Cys) variant in two siblings with variant A‐T at ages 22 and 20, diagnosed with gait ataxia or dystonia, respectively, but without immunodeficiency and with normal serum AFP (Albertyn et al, 2010). Furthermore, c.1066‐6T>G in conjunction with c.9022C>T was reported in a 48‐year‐old patient with a milder phenotype of A‐T and multiple myeloma (Austen et al, 2008).…”

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia‐Telangiectasia Mutated Gene

“…Her 20‐year‐old sister suffered from focal dystonia with retained autonomous walking. She showed ocular telangiectasia, whereas no immunodeficiency was detected and the AFP value was normal 15 . Despite the lack of definite data, they overall suggest a pathogenic tendency of the c.1066‐6T>G variant.…”

“…She showed ocular telangiectasia, whereas no immunodeficiency was detected and the AFP value was normal. 15 Despite the lack of definite data, they overall suggest a pathogenic tendency of the c.1066-6T>G variant. However, to avoid the potential contribution of concomitant polymorphisms and/or classically considered benign variants, such as those found in our family (Table 1), more genetically controlled assays, such as the generation of variant-specific cells by genome editing, are mandatory.…”