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.
  
  
  METHODS
  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.
authors.affiliation: Biomedical Informatics Division, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Abeer
authors.initials: A
authors.lastname: Fadda
authors.affiliation: Hamad Medical Corporation, Doha, Qatar.
authors.forename: Fiza
authors.initials: F
authors.lastname: Butt
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Sara
authors.initials: S
authors.lastname: Deola
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Bernice
authors.initials: B
authors.lastname: Lo
authors.affiliation: Weill Cornell Medicine in Qatar, Doha, Qatar.
authors.forename: Amal
authors.initials: A
authors.lastname: Robay
authors.affiliation: Weill Cornell Medicine in Qatar, Doha, Qatar.
authors.forename: Alya
authors.initials: A
authors.lastname: Al-Shakaki
authors.affiliation: Weill Cornell Medicine in Qatar, Doha, Qatar.
authors.forename: Noor
authors.initials: N
authors.lastname: Al-Hajri
authors.affiliation: Weill Cornell Medicine, New York, NY, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Crystal
authors.affiliation: Division of Genetics, Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Marios
authors.initials: M
authors.lastname: Kambouris
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.|Weill Cornell Medicine in Qatar, Doha, Qatar.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Fakhro
authors.affiliation: Division of Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar. ccugno@sidra.org.|SIDRA Medical and Research Center, Clinical Research Center, Out-Patient Clinic, Al Luqta Street, Education City, North Campus Qatar Foundation, PO Box 26999, Doha, Qatar. ccugno@sidra.org.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cugno
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D000072481:DNA Ligase ATP / Q000235:genetics*; D019066:Facies; D005260:Female; D016678:Genome / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000473:pathology; D016130:Immunophenotyping; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D014570:Urologic Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: C488673:LRIG2 protein, human; D008562:Membrane Glycoproteins; D000072481:DNA Ligase ATP
keywords: Case report; Immunodeficiency; LIG4; LRIG2; Microcephaly; Vesicoureteral reflux; Whole genome sequencing