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Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J, Boland JF, Burdett L, Brown C, Gatti RA, Alter BP, Biesecker LG, Savage SA - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.

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with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3).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.

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Sanger sequencing of LIG4 c.613delT variant in Patients 1 and 2.
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pone-0098686-g010: Sanger sequencing of LIG4 c.613delT variant in Patients 1 and 2.

Mentions: Exome sequencing with Sanger sequencing verification showed a known rare nonsense substitution predicted to result in a premature stop codon (rs104894419, NM_002312.3:c.2440C>T, p.Arg814X, MAF: 0.0002) and a single base pair deletion predicted a frameshift and premature stop codon (NM_002312.3:c.613delT; p.Ser205Leufs*29) (Figures 10 and 11). The rs104894419 variant had a MAF of 0.0002 in the ESP European-American cohort. The frameshift mutation had not been reported in 1000 Genomes, ESP or the ClinSeq databases. The two variants were in trans, consistent with autosomal recessive inheritance (Table S2). Western blotting showed absence of ligase IV band in both Patients 1 and 2 (Figure 12).


Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

Stewart DR, Pemov A, Johnston JJ, Sapp JC, Yeager M, He J, Boland JF, Burdett L, Brown C, Gatti RA, Alter BP, Biesecker LG, Savage SA - PLoS ONE (2014)

Sanger sequencing of LIG4 c.613delT variant in Patients 1 and 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4043752&req=5

pone-0098686-g010: Sanger sequencing of LIG4 c.613delT variant in Patients 1 and 2.
Mentions: Exome sequencing with Sanger sequencing verification showed a known rare nonsense substitution predicted to result in a premature stop codon (rs104894419, NM_002312.3:c.2440C>T, p.Arg814X, MAF: 0.0002) and a single base pair deletion predicted a frameshift and premature stop codon (NM_002312.3:c.613delT; p.Ser205Leufs*29) (Figures 10 and 11). The rs104894419 variant had a MAF of 0.0002 in the ESP European-American cohort. The frameshift mutation had not been reported in 1000 Genomes, ESP or the ClinSeq databases. The two variants were in trans, consistent with autosomal recessive inheritance (Table S2). Western blotting showed absence of ligase IV band in both Patients 1 and 2 (Figure 12).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus