Two hits in one

Whole genome sequencing unveils LIG4 syndrome and urofacial syndrome in a case report of a child with complex phenotype

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Ligase IV syndrome, a hereditary disease associated with compromised DNA damage response mechanisms, and Urofacial syndrome, caused by an impairment of neural cell signaling, are both rare genetic disorders, whose reports in literature are limited. We describe the first case combining both disorders in a specific phenotype. Case presentation: We report a case of a 7-year old girl presenting with a complex phenotype characterized by multiple congenital abnormalities and dysmorphic features, microcephaly, short stature, combined immunodeficiency and severe vesicoureteral reflux. Whole Genome Sequencing was performed and a novel ligase IV homozygous missense c.T1312C/p.Y438H mutation was detected, and is believed to be responsible for most of the clinical features of the child, except vesicoureteral reflux which has not been previously described for ligase IV deficiency. However, we observed a second rare damaging (nonsense) homozygous mutation (c.C2125T/p.R709X) in the leucine-rich repeats and immunoglobulin-like domains 2 gene that encodes a protein implicated in neural cell signaling and oncogenesis. Interestingly, this mutation has recently been reported as pathogenic and causing urofacial syndrome, typically displaying vesicoureteral reflux. Thus, this second mutation completes the missing genetic explanation for this intriguing clinical puzzle. We verified that both mutations fit an autosomal recessive inheritance model due to extensive consanguinity. Conclusions: We successfully identified a novel ligase IV mutation, causing ligase IV syndrome, and an additional rare leucine-rich repeats and immunoglobulin-like domains 2 gene nonsense mutation, in the context of multiple autosomal recessive conditions due to extensive consanguinity. This work demonstrates the utility of Whole Genome Sequencing data in clinical diagnosis in such cases where the combination of multiple rare phenotypes results in very intricate clinical pictures. It also reports a novel causative mutation and a clinical phenotype, which will help in better defining the essential features of both ligase IV and leucine-rich repeats and immunoglobulin-like domains 2 deficiency syndromes.

Original languageEnglish
Article number84
JournalBMC Medical Genetics
Volume17
Issue number1
DOIs
Publication statusPublished - 17 Nov 2016

Fingerprint

Ligases
Genome
Phenotype
Vesico-Ureteral Reflux
Mutation
Leucine
Consanguinity
Inborn Genetic Diseases
Nonsense Codon
Multiple Abnormalities
Severe Combined Immunodeficiency
Microcephaly
Genes
DNA Damage
Urofacial syndrome
LIG4 Syndrome
Carcinogenesis
Immunoglobulin Domains
Proteins

Keywords

  • Case report
  • Immunodeficiency
  • LIG4
  • LRIG2
  • Microcephaly
  • Vesicoureteral reflux
  • Whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

@article{140d1451a45e4a088d92562d1bbf1122,
title = "Two hits in one: Whole genome sequencing unveils LIG4 syndrome and urofacial syndrome in a case report of a child with complex phenotype",
abstract = "Background: Ligase IV syndrome, a hereditary disease associated with compromised DNA damage response mechanisms, and Urofacial syndrome, caused by an impairment of neural cell signaling, are both rare genetic disorders, whose reports in literature are limited. We describe the first case combining both disorders in a specific phenotype. Case presentation: We report a case of a 7-year old girl presenting with a complex phenotype characterized by multiple congenital abnormalities and dysmorphic features, microcephaly, short stature, combined immunodeficiency and severe vesicoureteral reflux. Whole Genome Sequencing was performed and a novel ligase IV homozygous missense c.T1312C/p.Y438H mutation was detected, and is believed to be responsible for most of the clinical features of the child, except vesicoureteral reflux which has not been previously described for ligase IV deficiency. However, we observed a second rare damaging (nonsense) homozygous mutation (c.C2125T/p.R709X) in the leucine-rich repeats and immunoglobulin-like domains 2 gene that encodes a protein implicated in neural cell signaling and oncogenesis. Interestingly, this mutation has recently been reported as pathogenic and causing urofacial syndrome, typically displaying vesicoureteral reflux. Thus, this second mutation completes the missing genetic explanation for this intriguing clinical puzzle. We verified that both mutations fit an autosomal recessive inheritance model due to extensive consanguinity. Conclusions: We successfully identified a novel ligase IV mutation, causing ligase IV syndrome, and an additional rare leucine-rich repeats and immunoglobulin-like domains 2 gene nonsense mutation, in the context of multiple autosomal recessive conditions due to extensive consanguinity. This work demonstrates the utility of Whole Genome Sequencing data in clinical diagnosis in such cases where the combination of multiple rare phenotypes results in very intricate clinical pictures. It also reports a novel causative mutation and a clinical phenotype, which will help in better defining the essential features of both ligase IV and leucine-rich repeats and immunoglobulin-like domains 2 deficiency syndromes.",
keywords = "Case report, Immunodeficiency, LIG4, LRIG2, Microcephaly, Vesicoureteral reflux, Whole genome sequencing",
author = "Fadda, {Abeer A.} and Fiza Butt and Sara Tomei and Sara Deola and Bernice Lo and Amal Robay and Alya Al-Shakaki and {Al Hajri}, Noor and Ronald Crystal and Marios Kambouris and Ena Wang and Marincola, {Francesco M.} and Fakhro, {Khalid Adnan Mohamed A.} and Chiara Cugno",
year = "2016",
month = "11",
day = "17",
doi = "10.1186/s12881-016-0346-7",
language = "English",
volume = "17",
journal = "BMC Medical Genetics",
issn = "1471-2350",
publisher = "BioMed Central",
number = "1",

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TY - JOUR

T1 - Two hits in one

T2 - Whole genome sequencing unveils LIG4 syndrome and urofacial syndrome in a case report of a child with complex phenotype

AU - Fadda, Abeer A.

AU - Butt, Fiza

AU - Tomei, Sara

AU - Deola, Sara

AU - Lo, Bernice

AU - Robay, Amal

AU - Al-Shakaki, Alya

AU - Al Hajri, Noor

AU - Crystal, Ronald

AU - Kambouris, Marios

AU - Wang, Ena

AU - Marincola, Francesco M.

AU - Fakhro, Khalid Adnan Mohamed A.

AU - Cugno, Chiara

PY - 2016/11/17

Y1 - 2016/11/17

N2 - Background: Ligase IV syndrome, a hereditary disease associated with compromised DNA damage response mechanisms, and Urofacial syndrome, caused by an impairment of neural cell signaling, are both rare genetic disorders, whose reports in literature are limited. We describe the first case combining both disorders in a specific phenotype. Case presentation: We report a case of a 7-year old girl presenting with a complex phenotype characterized by multiple congenital abnormalities and dysmorphic features, microcephaly, short stature, combined immunodeficiency and severe vesicoureteral reflux. Whole Genome Sequencing was performed and a novel ligase IV homozygous missense c.T1312C/p.Y438H mutation was detected, and is believed to be responsible for most of the clinical features of the child, except vesicoureteral reflux which has not been previously described for ligase IV deficiency. However, we observed a second rare damaging (nonsense) homozygous mutation (c.C2125T/p.R709X) in the leucine-rich repeats and immunoglobulin-like domains 2 gene that encodes a protein implicated in neural cell signaling and oncogenesis. Interestingly, this mutation has recently been reported as pathogenic and causing urofacial syndrome, typically displaying vesicoureteral reflux. Thus, this second mutation completes the missing genetic explanation for this intriguing clinical puzzle. We verified that both mutations fit an autosomal recessive inheritance model due to extensive consanguinity. Conclusions: We successfully identified a novel ligase IV mutation, causing ligase IV syndrome, and an additional rare leucine-rich repeats and immunoglobulin-like domains 2 gene nonsense mutation, in the context of multiple autosomal recessive conditions due to extensive consanguinity. This work demonstrates the utility of Whole Genome Sequencing data in clinical diagnosis in such cases where the combination of multiple rare phenotypes results in very intricate clinical pictures. It also reports a novel causative mutation and a clinical phenotype, which will help in better defining the essential features of both ligase IV and leucine-rich repeats and immunoglobulin-like domains 2 deficiency syndromes.

AB - Background: Ligase IV syndrome, a hereditary disease associated with compromised DNA damage response mechanisms, and Urofacial syndrome, caused by an impairment of neural cell signaling, are both rare genetic disorders, whose reports in literature are limited. We describe the first case combining both disorders in a specific phenotype. Case presentation: We report a case of a 7-year old girl presenting with a complex phenotype characterized by multiple congenital abnormalities and dysmorphic features, microcephaly, short stature, combined immunodeficiency and severe vesicoureteral reflux. Whole Genome Sequencing was performed and a novel ligase IV homozygous missense c.T1312C/p.Y438H mutation was detected, and is believed to be responsible for most of the clinical features of the child, except vesicoureteral reflux which has not been previously described for ligase IV deficiency. However, we observed a second rare damaging (nonsense) homozygous mutation (c.C2125T/p.R709X) in the leucine-rich repeats and immunoglobulin-like domains 2 gene that encodes a protein implicated in neural cell signaling and oncogenesis. Interestingly, this mutation has recently been reported as pathogenic and causing urofacial syndrome, typically displaying vesicoureteral reflux. Thus, this second mutation completes the missing genetic explanation for this intriguing clinical puzzle. We verified that both mutations fit an autosomal recessive inheritance model due to extensive consanguinity. Conclusions: We successfully identified a novel ligase IV mutation, causing ligase IV syndrome, and an additional rare leucine-rich repeats and immunoglobulin-like domains 2 gene nonsense mutation, in the context of multiple autosomal recessive conditions due to extensive consanguinity. This work demonstrates the utility of Whole Genome Sequencing data in clinical diagnosis in such cases where the combination of multiple rare phenotypes results in very intricate clinical pictures. It also reports a novel causative mutation and a clinical phenotype, which will help in better defining the essential features of both ligase IV and leucine-rich repeats and immunoglobulin-like domains 2 deficiency syndromes.

KW - Case report

KW - Immunodeficiency

KW - LIG4

KW - LRIG2

KW - Microcephaly

KW - Vesicoureteral reflux

KW - Whole genome sequencing

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DO - 10.1186/s12881-016-0346-7

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JO - BMC Medical Genetics

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SN - 1471-2350

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