Analyses of LMNA-negative Juvenile Progeroid Cases Confirms Biallelic POLR3A Mutations in Wiedemann-Rautenstrauch-like Syndrome and Expands the Phenotypic Spectrum of PYCR1 Mutations

Hum Genet. 2018 Dec;137(11-12):921-939. doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.

Abstract

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

Keywords: Hutchinson–Gilford progeria syndrome; Juvenile segmental progeroid syndrome; POLR3A; PYCR1; Wiedemann–Rautenstrauch progeroid syndrome.

MeSH terms

  • Adolescent
  • Alternative Splicing / genetics
  • Child
  • Female
  • Fetal Growth Retardation / diagnosis
  • Fetal Growth Retardation / genetics*
  • Fetal Growth Retardation / pathology
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Lamin Type A / genetics
  • Male
  • Mutation
  • Phenotype
  • Progeria / diagnosis
  • Progeria / genetics*
  • Progeria / pathology
  • Progeria / physiopathology
  • Pyrroline Carboxylate Reductases / genetics*
  • RNA Polymerase III / genetics*

Substances

  • LMNA protein, human
  • Lamin Type A
  • prelamin A
  • Pyrroline Carboxylate Reductases
  • delta-1-pyrroline-5-carboxylate reductase
  • POLR3A protein, human
  • RNA Polymerase III

Supplementary concepts

  • Progeroid syndrome, neonatal