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:
CreatorsEmailORCIDORCID Put Code
Murray, Jennie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bicknell, Louise S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duker, Angela L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Kogelenberg, MargrietUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haghayegh, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDorcid.org/0000-0003-2812-6492UNSPECIFIED
Kayserili, HuelyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albert, Michael H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wise, Carol A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandon, JanuaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleefstra, TjitskeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warris, AdiliaUNSPECIFIEDorcid.org/0000-0001-6586-3358UNSPECIFIED
van der Flier, MichielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bamforth, J. StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doonanco, KurstonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ades, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Field, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shackley, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Firth, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woods, C. GeoffreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gatti, Richard A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hurles, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bober, Michael B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, Andrew P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
STRAND BREAK REPAIR; SEVERE COMBINED IMMUNODEFICIENCY; DNA-LIGASE; ATAXIA-TELANGIECTASIA; LIG4 SYNDROME; MUTATIONS; PROTEIN; XRCC4; RECOMBINATION; PATIENTMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/45225

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