A girl with an atypical form of ataxia telangiectasia and an additional de novo 3.14 Mb microduplication in region 19q12

• Published in: European journal of medical genetics Vol. 55; no. 1; pp. 49 - 55
• Main Authors: Bartsch, Oliver, Schindler, Detlev, Beyer, Vera, Gesk, Stefan, van’t Slot, Ruben, Feddersen, Isa, Buijs, Arjan, Jaspers, Nicolaas G.J, Siebert, Reiner, Haaf, Thomas, Poot, Martin
• Format: Journal Article
• Language: English
• Published: Netherlands 01-01-2012
• Subjects: Apoptosis Regulatory Proteins - genetics; Ataxia Telangiectasia - diagnosis; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia - pathology; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - genetics; Child; Chromosome Duplication; Chromosome Inversion; Chromosomes, Human, Pair 19 - genetics; DNA Damage; DNA-Binding Proteins - genetics; Female; Humans; Lymphocytes - cytology; Medical Education; Mental Disorders - genetics; Mental Disorders - pathology; Metaphase; Microcephaly - genetics; Microcephaly - pathology; Protein-Serine-Threonine Kinases - genetics; Saliva - cytology; Tumor Suppressor Proteins - genetics; Ubiquinol-cytochrome c reductase gene UQCRFS1; Ataxia telangiectasia; Oligoarthritis; Inversion inv(q11q32); Pleckstrin homology domain-containing gene PLEKHF1; Muscular weakness; Duplication 19q12; Mental retardation; Speech delay; Mosaic
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2011.08.001

Abstract A 9-year-old girl born to healthy parents showed manifestations suggestive of ataxia telangiectasia (AT), such as short stature, sudden short bouts of horizontal and rotary nystagmus, a weak and dysarthric voice, rolling gait, unstable posture, and atactic movements. She did not show several cardinal features typical of AT such as frequent, severe infections of the respiratory tract. In contrast, she showed symptoms not generally related to AT, including microcephaly, profound motor and mental retardation, small hands and feet, severely and progressively reduced muscle tone with slackly protruding abdomen and undue drooling, excess fat on her upper arms, and severe oligoarthritis. A cranial MRI showed no cerebellar hypoplasia and other abnormalities. In peripheral blood samples she carried a de novo duplication of 3.14 Mb in chromosomal region 19q12 containing six annotated genes, UQCRFS1 , VSTM2B , POP4 , PLEKHF1 , CCNE1 , and ZNF536 , and a de novo mosaic inversion 14q11q32 (96% of metaphases). In a saliva-derived DNA sample only the duplication in 19q12 was detected, suggesting that the rearrangements in blood lymphocytes were acquired. These findings reinforced the suspicion that she had AT. AT was confirmed by strongly elevated serum AFP levels, cellular radiosensitivity and two inherited mutations in the ATM gene (c.510_511delGT; paternal origin and c.2922-50_2940del69; maternal origin). This case suggest that a defective ATM-dependent DNA damage response may entail additional stochastic genomic rearrangements. Screening for genomic rearrangements appears indicated in patients suspected of defective DNA damage responses.