Homozygosity mapping identifies a bile acid biosynthetic defect in an adult with cirrhosis of unknown etiology

Abstract

The most common inborn error of bile acid metabolism is 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency, a disorder that usually presents in early childhood with hepatic dysfunction. Timely diagnosis of this disorder is crucial since it can be effectively treated with primary bile acid replacement. Here we describe a 24-year-old woman from Iran with cirrhosis of unknown etiology. Her sister and a first cousin died of cirrhosis (ages 19 and 6 years) and another 32-year old first cousin had a self-limited liver disorder in childhood that resolved at age 9 years. The family history was consistent with the notion that affected family members were homozygous for a mutant allele inherited identical-by-descent. A genome-wide analysis of 2.5 million single nucleotide polymorphisms (SNP) was performed to identify regions of homozygosity that were present in the proband and the 32-year old first cousin, but not in a healthy relative. One of these regions contained the gene encoding 3β-HSD (HSD3B7). Sequence analysis of HSD3B7 revealed that the proband and her 32-year old cousin were homozygous for a frame shift mutation (c.45_46del AG, p.T15Tfsx27) in exon 1. The diagnosis of 3β-HSD deficiency was confirmed by documenting high levels of 3β-hydroxy-Δ5 bile acids in the serum of the first cousin using mass spectrometry. To our knowledge, the 32-year old relative in this family represents the oldest asymptomatic patient with this disorder. Conclusion: This study highlights the clinical utility of homozygosity mapping in diagnosing autosomal recessive metabolic disorders. This family illustrates the wide variation in expressivity that occurs in 3β-HSD deficiency and underscores the need to consider a bile acid synthetic defect as a possible cause of liver disease in adults.

Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders

“…The histologic findings in the present study, although limited, are consistent with previous reports, which showed either improved or stabilized inflammation and fibrosis with therapy (5,13,15). It is important to note that the presenting symptoms and signs in patients with SED may be quite variable (20) and may appear from infancy through adulthood (21,22). Patients with 5b-reductase deficiency tended to present at a younger age (median age, 3 months) with marked biochemical abnormalities compared with those presenting with 3b-HSD deficiency, many of whom presented at a later age (median age, 37 months) with evidence of liver fibrosis but less impressive biochemical abnormalities.…”

Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders

“…The histologic findings in the present study, although limited, are consistent with previous reports, which showed either improved or stabilized inflammation and fibrosis with therapy ( 5 , 13 , 15 ). It is important to note that the presenting symptoms and signs in patients with SED may be quite variable ( 20 ) and may appear from infancy through adulthood ( 21 , 22 ). Patients with 5β-reductase deficiency tended to present at a younger age (median age, 3 months) with marked biochemical abnormalities compared with those presenting with 3β-HSD deficiency, many of whom presented at a later age (median age, 37 months) with evidence of liver fibrosis but less impressive biochemical abnormalities.…”

Hunting human disease genes: lessons from the past, challenges for the future

“…This strategy can efficiently identify genomic regions in which candidate genes can then be tested for the presence of pathogenic mutations. Homozygosity mapping has recently been used in combination with high-density whole genome genotyping to identify disease genes in patients in whom homozygosity by descent is suspected (Molho-Pessach et al 2012). …”