Universität zu Köln

Schroeder, Simone, Wieland, Britta, Ohlenbusch, Andreas, Yigit, Goekhan, Altmueller, Janine, Boltshauser, Eugen, Doerk, Thilo and Brockmann, Knut (2020). Evidence of pathogenicity for the leaky splice variant c.1066-6T>G inATM. Am. J. Med. Genet. A, 182 (12). S. 2971 - 2976. HOBOKEN: WILEY. ISSN 1552-4833

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Abstract

Mild clinical phenotypes of ataxia-telangiectasia (variant A-T) are associated with biallelicATMvariants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A-T. Studies on the pathogenicity of the germline splicingATMvariant c.1066-6T>G have provided conflicting results. Using whole-exome sequencing, we identified two splice siteATMvariants, c.1066-6T>G; [p.?], and c.2250G>A, [p.Ile709_Lys750del], in a compound heterozygous state in a 27-year-old woman who had been diagnosed as having congenital ocular motor apraxia type Cogan in her childhood. Reappraisal of her clinical phenotype revealed consistency with variant A-T. Functional analyses showed reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant A-T. Our results provide evidence for pathogenicity of the leakyATMsplice site variant c.1066-6T>G.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schroeder, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Wieland, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Ohlenbusch, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Boltshauser, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerk, Thilo UNSPECIFIED UNSPECIFIED UNSPECIFIED Brockmann, Knut UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-319327
DOI:	10.1002/ajmg.a.61870
Journal or Publication Title:	Am. J. Med. Genet. A
Volume:	182
Number:	12
Page Range:	S. 2971 - 2976
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1552-4833
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ATM GENE-MUTATIONS; ATAXIA-TELANGIECTASIA; HETEROZYGOTES; GENOTYPE; MISSENSE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31932