Universität zu Köln

Murray, Jennie E., Bicknell, Louise S., Yigit, Goekhan, Duker, Angela L., van Kogelenberg, Margriet, Haghayegh, Sara, Wieczorek, Dagmar ORCID: 0000-0003-2812-6492, Kayserili, Huelya, Albert, Michael H., Wise, Carol A., Brandon, January, Kleefstra, Tjitske, Warris, Adilia ORCID: 0000-0001-6586-3358, van der Flier, Michiel, Bamforth, J. Steven, Doonanco, Kurston, Ades, Lesley, Ma, Alan, Field, Michael, Johnson, Diana, Shackley, Fiona, Firth, Helen, Woods, C. Geoffrey, Nuernberg, Peter, Gatti, Richard A., Hurles, Matthew, Bober, Michael B., Wollnik, Bernd and Jackson, Andrew P. (2014). Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Hum. Mutat., 35 (1). S. 76 - 86. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype-phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder. Published 2013 Wiley Periodicals, Inc.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Murray, Jennie E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bicknell, Louise S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Duker, Angela L. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Kogelenberg, Margriet UNSPECIFIED UNSPECIFIED UNSPECIFIED Haghayegh, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Wieczorek, Dagmar UNSPECIFIED orcid.org/0000-0003-2812-6492 UNSPECIFIED Kayserili, Huelya UNSPECIFIED UNSPECIFIED UNSPECIFIED Albert, Michael H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wise, Carol A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandon, January UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleefstra, Tjitske UNSPECIFIED UNSPECIFIED UNSPECIFIED Warris, Adilia UNSPECIFIED orcid.org/0000-0001-6586-3358 UNSPECIFIED van der Flier, Michiel UNSPECIFIED UNSPECIFIED UNSPECIFIED Bamforth, J. Steven UNSPECIFIED UNSPECIFIED UNSPECIFIED Doonanco, Kurston UNSPECIFIED UNSPECIFIED UNSPECIFIED Ades, Lesley UNSPECIFIED UNSPECIFIED UNSPECIFIED Ma, Alan UNSPECIFIED UNSPECIFIED UNSPECIFIED Field, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Johnson, Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Shackley, Fiona UNSPECIFIED UNSPECIFIED UNSPECIFIED Firth, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Woods, C. Geoffrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Gatti, Richard A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hurles, Matthew UNSPECIFIED UNSPECIFIED UNSPECIFIED Bober, Michael B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Jackson, Andrew P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-452253
DOI:	10.1002/humu.22461
Journal or Publication Title:	Hum. Mutat.
Volume:	35
Number:	1
Page Range:	S. 76 - 86
Date:	2014
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STRAND BREAK REPAIR; SEVERE COMBINED IMMUNODEFICIENCY; DNA-LIGASE; ATAXIA-TELANGIECTASIA; LIG4 SYNDROME; MUTATIONS; PROTEIN; XRCC4; RECOMBINATION; PATIENT Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/45225