title: Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.
abstract: Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stewart
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pemov
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Sapp
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Ji
authors.initials: J
authors.lastname: He
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Brown
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America; Department of Human Genetics, David Geffen UCLA School of Medicine, Los Angeles, California, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000328:Adult; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics; D004485:Eczema / Q000175:diagnosis* / Q000235:genetics*; D019066:Facies; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D018740:Genetic Heterogeneity; D005838:Genotype; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016615:Telomere / Q000235:genetics