Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

Jennie E. Murray, Louise S. Bicknell, Gökhan Yigit, Angela L. Duker, Margriet van Kogelenberg, Sara Haghayegh, Dagmar Wieczorek, Hülya Kayserili, Michael H. Albert, Carol A. Wise, January Brandon, Tjitske Kleefstra, Adilia Warris, Michiel van der Flier, J Steven Bamforth, Kurston Doonanco, Lesley Adès, Alan Ma, Michael Field, Diana Johnson & 9 others Fiona Shackley, Helen Firth, C. Geoffrey Woods, Peter Nürnberg, Richard A. Gatti, Matthew Hurles, Michael B. Bober, Bernd Wollnik, Andrew P. Jackson

Research output: Contribution to journalArticle

48 Citations (Scopus)
3 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)76-85
Number of pages10
JournalHuman Mutation
Volume35
Issue number1
Early online date8 Nov 2013
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Ligases
Mutation
Growth
Microcephaly
Neoplasms
Nijmegen Breakage Syndrome
Dwarfism
Severe Combined Immunodeficiency
Radiation Tolerance
Leukopenia
Genetic Association Studies
Thrombocytopenia
Hypersensitivity
Differential Diagnosis
Bone Marrow
Radiation
Phenotype
Mortality

Keywords

  • ligase IV
  • LIG4
  • nonhomologous end joining
  • radiosensitivity
  • cytopenia
  • malignancy
  • DNA repair
  • immunodeficiency

Cite this

Murray, J. E., Bicknell, L. S., Yigit, G., Duker, A. L., van Kogelenberg, M., Haghayegh, S., ... Jackson, A. P. (2014). Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Human Mutation, 35(1), 76-85. https://doi.org/10.1002/humu.22461

Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. / Murray, Jennie E.; Bicknell, Louise S.; Yigit, Gökhan; Duker, Angela L.; van Kogelenberg, Margriet; Haghayegh, Sara; Wieczorek, Dagmar; Kayserili, Hülya; Albert, Michael H.; Wise, Carol A.; Brandon, January; Kleefstra, Tjitske; Warris, Adilia; van der Flier, Michiel; Bamforth, J Steven; Doonanco, Kurston; Adès, Lesley; Ma, Alan; Field, Michael; Johnson, Diana; Shackley, Fiona; Firth, Helen; Woods, C. Geoffrey; Nürnberg, Peter; Gatti, Richard A.; Hurles, Matthew; Bober, Michael B.; Wollnik, Bernd; Jackson, Andrew P.

In: Human Mutation, Vol. 35, No. 1, 01.2014, p. 76-85.

Research output: Contribution to journalArticle

Murray, JE, Bicknell, LS, Yigit, G, Duker, AL, van Kogelenberg, M, Haghayegh, S, Wieczorek, D, Kayserili, H, Albert, MH, Wise, CA, Brandon, J, Kleefstra, T, Warris, A, van der Flier, M, Bamforth, JS, Doonanco, K, Adès, L, Ma, A, Field, M, Johnson, D, Shackley, F, Firth, H, Woods, CG, Nürnberg, P, Gatti, RA, Hurles, M, Bober, MB, Wollnik, B & Jackson, AP 2014, 'Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency', Human Mutation, vol. 35, no. 1, pp. 76-85. https://doi.org/10.1002/humu.22461
Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M, Haghayegh S et al. Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. Human Mutation. 2014 Jan;35(1):76-85. https://doi.org/10.1002/humu.22461
Murray, Jennie E. ; Bicknell, Louise S. ; Yigit, Gökhan ; Duker, Angela L. ; van Kogelenberg, Margriet ; Haghayegh, Sara ; Wieczorek, Dagmar ; Kayserili, Hülya ; Albert, Michael H. ; Wise, Carol A. ; Brandon, January ; Kleefstra, Tjitske ; Warris, Adilia ; van der Flier, Michiel ; Bamforth, J Steven ; Doonanco, Kurston ; Adès, Lesley ; Ma, Alan ; Field, Michael ; Johnson, Diana ; Shackley, Fiona ; Firth, Helen ; Woods, C. Geoffrey ; Nürnberg, Peter ; Gatti, Richard A. ; Hurles, Matthew ; Bober, Michael B. ; Wollnik, Bernd ; Jackson, Andrew P. / Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency. In: Human Mutation. 2014 ; Vol. 35, No. 1. pp. 76-85.
@article{c7171d8141284e6ea59c81c35b4e26d1,
title = "Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency",
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.",
keywords = "ligase IV, LIG4, nonhomologous end joining, radiosensitivity, cytopenia, malignancy, DNA repair, immunodeficiency",
author = "Murray, {Jennie E.} and Bicknell, {Louise S.} and G{\"o}khan Yigit and Duker, {Angela L.} and {van Kogelenberg}, Margriet and Sara Haghayegh and Dagmar Wieczorek and H{\"u}lya Kayserili and Albert, {Michael H.} and Wise, {Carol A.} and January Brandon and Tjitske Kleefstra and Adilia Warris and {van der Flier}, Michiel and Bamforth, {J Steven} and Kurston Doonanco and Lesley Ad{\`e}s and Alan Ma and Michael Field and Diana Johnson and Fiona Shackley and Helen Firth and Woods, {C. Geoffrey} and Peter N{\"u}rnberg and Gatti, {Richard A.} and Matthew Hurles and Bober, {Michael B.} and Bernd Wollnik and Jackson, {Andrew P.}",
note = "We thank Stephen Brown and Agnes Gallagher for technical support. A.P.J. is a MRC Senior Clinical Fellow and Lister Institute for Preventative MedicinePrize Fellow. Disclosure statement: The authors declare no conflict of interest. Funded by MRC Wellcome Trust. Grant Number: WT098051 Texas Scottish Rite Hospital for Children Research Fund Potentials Foundation and Walking With Giants Foundation (WWGF)",
year = "2014",
month = "1",
doi = "10.1002/humu.22461",
language = "English",
volume = "35",
pages = "76--85",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

AU - Murray, Jennie E.

AU - Bicknell, Louise S.

AU - Yigit, Gökhan

AU - Duker, Angela L.

AU - van Kogelenberg, Margriet

AU - Haghayegh, Sara

AU - Wieczorek, Dagmar

AU - Kayserili, Hülya

AU - Albert, Michael H.

AU - Wise, Carol A.

AU - Brandon, January

AU - Kleefstra, Tjitske

AU - Warris, Adilia

AU - van der Flier, Michiel

AU - Bamforth, J Steven

AU - Doonanco, Kurston

AU - Adès, Lesley

AU - Ma, Alan

AU - Field, Michael

AU - Johnson, Diana

AU - Shackley, Fiona

AU - Firth, Helen

AU - Woods, C. Geoffrey

AU - Nürnberg, Peter

AU - Gatti, Richard A.

AU - Hurles, Matthew

AU - Bober, Michael B.

AU - Wollnik, Bernd

AU - Jackson, Andrew P.

N1 - We thank Stephen Brown and Agnes Gallagher for technical support. A.P.J. is a MRC Senior Clinical Fellow and Lister Institute for Preventative MedicinePrize Fellow. Disclosure statement: The authors declare no conflict of interest. Funded by MRC Wellcome Trust. Grant Number: WT098051 Texas Scottish Rite Hospital for Children Research Fund Potentials Foundation and Walking With Giants Foundation (WWGF)

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - ligase IV

KW - LIG4

KW - nonhomologous end joining

KW - radiosensitivity

KW - cytopenia

KW - malignancy

KW - DNA repair

KW - immunodeficiency

U2 - 10.1002/humu.22461

DO - 10.1002/humu.22461

M3 - Article

VL - 35

SP - 76

EP - 85

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 1

ER -