Atypical Werner Syndrome Suggestive of Synergistic Effects of Werner, Perilipin, and a Rare Balanced Translocation
Werner syndrome (WS; OMIM 277700) is an accelerated aging syndrome with characteristic features of “normal aging process” presenting in the second decade of life associated with cataracts, premature graying and thinning of hair, dermatological abnormality, and short stature as cardinal features. Lipodystrophy is a heterogeneous disorders manifesting with a loss of subcutaneous adiposity from the entire body or from the extremities, and a deposition of excess adiposity in other areas such as in the liver. It is often associated with hypertriglyceridemia, diabetes mellitus, and fatty liver which are reminiscent of “common” metabolic syndrome with or without abnormalities in the heart, kidneys, skin, and/or autoimmune system. Atherosclerotic vascular disease may be a serious feature in WS or lipodystrophy.
Here, we present a 43-year-old man with an aged appearance with thinning gray hair, bilateral cataracts, severe peripheral vasculopathy with extensive calcifications requiring multiple stents, diabetes mellitus, hypertriglyceridemia, and fatty liver. He has a short stature (1.67 m) with low body weight (48.1 kg), and BMI (17.1 kg/m2). There are no other family members with similar body habitus or clinical features. In addition, the proband, his mother and two sons carry a previously identified “balanced” translocation t(8;10)(q13;q23.2).
A next-generation sequencing (NGS) panel targeting 19 known premature aging and lipodystrophy associated genes and follow-up Sanger sequencing identified in the proband a heterozygous pathogenic mutation in WRN (c.2665C>T, p.R889X), encoding a DNA helicase responsible for classical recessive WS, and an extremely rare homozygous variant in PLIN1 (c.107G>T, p.C36F), encoding perilipin, a lipid droplet surface protein.
Fine mapping of the breakpoints of the translocation t(8;10)(q13;q23.2) by a novel linked-read technology to localize structural alterations and subsequent Sanger sequencing of the regions revealed one breakpoint at Chr10:94,851,229 and Chr8:67,299,332 (hg19), and another at Chr8:67,299,224 and Chr10:94,851,255 (hg19). Both breakpoints are found within Alu elements in Chr8 and Chr10. Interestingly, further investigation identified four genes, ADHFE1 located telomeric to the breakpoint on Chr8, and CYP26A1,and CYP26C1 located centromeric to the breakpoint on Chr10, which may influence adipocyte, cholesterol, or fatty acid metabolism. In addition, we were able to assess that there were no grossly identifiable copy number variations in WRN.
Analyses of the family members showed that the proband’s healthy two sons also had genetic alterations at the three loci (WRN, PLIN1, and Chr8:Chr10), except they carried PLIN1 mutation in only one allele. The proband’s two brothers were found to have the homozygous PLIN1 variant, but neither carried the WRN allele nor the translocation. Therefore, the proband is the only one in the family who is a WRN carrier as well as with the homozygous PLIN1 variant and the translocation.
The proband has clinical features consistent with WS, albeit with a later onset than typically described. Classical WS involving WRN is biallelic, where WRN carriers are reportedly asymptomatic. For PLIN1, only heterozygous splicing or deletion, never a missense variant, has been described with lipodystrophy (FPLD4; OMIM 613877). In addition, the brothers who are PLIN1 homozygous do not have the typical body habitus of lipodystrophy. Unfortunately, no one has the translocation in isolation to assess its phenotypic effects.
One possible hypothesis for the proband’s impressive Werner clinical features with lipodystrophy may be due to synergistic effects of the three genetic alterations with predominance of the WRN mutation. The genes identified near the translocation breakpoints may be modifying the expressions of WRN and PLIN1. Further studies to assess the WRN protein expression, PLIN1 functionality, and expression of the genes near the breakpoints on Chr8 and Chr10 may help in elucidating the contribution of each genetic alteration.