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Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia.

Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC - Hum. Mol. Genet. (2010)

Bottom Line: This finding indicated that the infant has sitosterolemia.Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned.These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

View Article: PubMed Central - PubMed

Affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas,TX 75390, USA.

ABSTRACT
Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

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Pedigree of an infant with severe hypercholesterolemia who presented with cutaneous xanthomas. (A) Pictures taken at presentation of cutaneous (planar) xanthomas in the creases of the Achilles region. Note the orange-yellow hue of the xanthomas. (B) The proband was a 1-year-old offspring of an unrelated Romanian couple who had no family history of hypercholesterolemia or of premature coronary artery disease. The child was being breast-fed when a plasma sample was obtained and sent to Dallas, TX, USA. The total cholesterol and triglycerides were measured enzymatically, and the lipoproteins were quantitated by beta-quantification. Neutral sterols were analyzed using liquid GC/MS, and the plasma sitosterol and campesterol were expressed as a fraction of total cholesterol (TC).
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DDQ352F1: Pedigree of an infant with severe hypercholesterolemia who presented with cutaneous xanthomas. (A) Pictures taken at presentation of cutaneous (planar) xanthomas in the creases of the Achilles region. Note the orange-yellow hue of the xanthomas. (B) The proband was a 1-year-old offspring of an unrelated Romanian couple who had no family history of hypercholesterolemia or of premature coronary artery disease. The child was being breast-fed when a plasma sample was obtained and sent to Dallas, TX, USA. The total cholesterol and triglycerides were measured enzymatically, and the lipoproteins were quantitated by beta-quantification. Neutral sterols were analyzed using liquid GC/MS, and the plasma sitosterol and campesterol were expressed as a fraction of total cholesterol (TC).

Mentions: The proband for this study was a healthy 11-month-old girl who presented with subcutaneous xanthomas over the Achilles tendon (Fig. 1A). Her plasma cholesterol level was 1023 mg/dl with an LDL-C of 837 mg/dl, HDL-C of 54 mg/dl and triglyceride of 120 mg/dl. Thyroid function and liver function tests were normal as was her urinalysis. A pedigree of the proband's family, with plasma lipid and lipoprotein levels determined 1 month after presentation, is shown in Figure 1B. The proband was born to unrelated Romanian parents after an unremarkable pregnancy. The plasma lipid levels of both parents were within the normal range. The child was exclusively breast-fed for the first 6 months of life and then was slowly weaned off breast milk. At the time of diagnosis, breast milk comprised 80% of her dietary intake.Figure 1.


Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia.

Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC - Hum. Mol. Genet. (2010)

Pedigree of an infant with severe hypercholesterolemia who presented with cutaneous xanthomas. (A) Pictures taken at presentation of cutaneous (planar) xanthomas in the creases of the Achilles region. Note the orange-yellow hue of the xanthomas. (B) The proband was a 1-year-old offspring of an unrelated Romanian couple who had no family history of hypercholesterolemia or of premature coronary artery disease. The child was being breast-fed when a plasma sample was obtained and sent to Dallas, TX, USA. The total cholesterol and triglycerides were measured enzymatically, and the lipoproteins were quantitated by beta-quantification. Neutral sterols were analyzed using liquid GC/MS, and the plasma sitosterol and campesterol were expressed as a fraction of total cholesterol (TC).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2957323&req=5

DDQ352F1: Pedigree of an infant with severe hypercholesterolemia who presented with cutaneous xanthomas. (A) Pictures taken at presentation of cutaneous (planar) xanthomas in the creases of the Achilles region. Note the orange-yellow hue of the xanthomas. (B) The proband was a 1-year-old offspring of an unrelated Romanian couple who had no family history of hypercholesterolemia or of premature coronary artery disease. The child was being breast-fed when a plasma sample was obtained and sent to Dallas, TX, USA. The total cholesterol and triglycerides were measured enzymatically, and the lipoproteins were quantitated by beta-quantification. Neutral sterols were analyzed using liquid GC/MS, and the plasma sitosterol and campesterol were expressed as a fraction of total cholesterol (TC).
Mentions: The proband for this study was a healthy 11-month-old girl who presented with subcutaneous xanthomas over the Achilles tendon (Fig. 1A). Her plasma cholesterol level was 1023 mg/dl with an LDL-C of 837 mg/dl, HDL-C of 54 mg/dl and triglyceride of 120 mg/dl. Thyroid function and liver function tests were normal as was her urinalysis. A pedigree of the proband's family, with plasma lipid and lipoprotein levels determined 1 month after presentation, is shown in Figure 1B. The proband was born to unrelated Romanian parents after an unremarkable pregnancy. The plasma lipid levels of both parents were within the normal range. The child was exclusively breast-fed for the first 6 months of life and then was slowly weaned off breast milk. At the time of diagnosis, breast milk comprised 80% of her dietary intake.Figure 1.

Bottom Line: This finding indicated that the infant has sitosterolemia.Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned.These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

View Article: PubMed Central - PubMed

Affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas,TX 75390, USA.

ABSTRACT
Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

Show MeSH
Related in: MedlinePlus