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

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.

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

“…However, all four cases showed great reductions in serum cholesterol levels immediately after weaning, which would not have been observed in homozygous FH. Rios et al reported an 11-month-old girl with compound heterozygous sitosterolaemia due to ABCG5 gene mutations who showed extreme hypercholesterolaemia (serum TC level, 1,023 mg/dl) (Rios et al 2010). Her cholesterol levels also dramatically decreased after weaning, as with our cases.…”

“…Clinical and Laboratory Characteristics of Infantile Cases with Sitosterolaemia (Table 1) We have summarised clinical and laboratory characteristics of infantile cases with sitosterolaemia of ours and those from the literature (Niu et al 2010;Park et al 2014;Rios et al 2010) in Table 1, focusing on the changes in clinical manifestations before and after the weaning. Most of the infantile cases with sitosterolaemia exhibited intertriginous xanthomas associated with extremely high LDL cholesterolaemia during breastfeeding, which decreased dramatically after weaning.…”

Clinical utility gene card for: Sitosterolaemia

“…5,6 In addition, some patients can present with haematological abnormalities including macrothrombocytopenia, stomatocytes, haemolytic anaemia and splenomegaly. 7,8 Very rare patients can present primarily with elevated plasma levels of lowdensity lipoprotein cholesterol and cutaneous xanthomas, expressing a phenotype that resembles heterozygous familial hypercholesterolaemia (FH), 9 and in severe cases, resembling homozygous FH, with coronary disease in childhood and adolescence. 10,11 The condition should be considered even when consumption of plant sterols has not commenced, as phytosterols can be found in breast milk.…”

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

“…So far, all the discoveries made by wholegenome sequencing could also have been achieved using exome sequencing for Mendelian disorders. 110,111 Furthermore, the genetic variants in most of the non-coding regions revealed by wholegenome sequencing remain 'uninterpretable' biologically. In taking a practical (rather than theoretical) point of view, whole-genome sequencing still presents a very substantial technical challenge as well as a challenge in terms of analyzing and interpreting the sequence data generated.…”