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, 137 (11-12), 921-939

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

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

Davor Lessel et al. Hum Genet.

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.

Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Clinical characteristics of POLR3A-mutated individuals. Facial images of individual 1 at age 4 months, 1.5 years and 2 years and 10 months (a), individual 4 at the age of 1 year and 7 months, and 3 years (b), and individual 11 from the birth till 11 months (c)
Fig. 2
Fig. 2
Clinical characteristics of PYCR1-mutated individuals. Facial images of individual 2 at 1.5 years and 9 years (a), individual 7 at the age of 10 months and 1.5 years (b), individual 13 at birth and 6 weeks (c), and individual 14 at 6 months (d)
Fig. 3
Fig. 3
Clinical characteristics of COL1A1-mutated individual and the two unclassified juvenile progeroid individuals. Facial images of individual 3 bearing the de novo COL1A1 mutation at age 8 months and 1 year (a), individual 8 at the age of 1 year and 3 years (b), and individual 9 at 13.5 years (c)
Fig. 4
Fig. 4
POLR3A splicing defect caused by c.3337-5T > A mutation results in skipping of exon 26. Agarose gel electrophoresis of POLR3A RT-PCR products. The proband and father both carry the c.3337-5T > A mutation, resulting in a smaller band of ~ 287 bp corresponding to a cDNA missing exon 26 compared to the size of the wild-type band of ~ 380 bp (a). Sanger sequence traces of gel-extracted POLR3A RT-PCR products, demonstrating wild-type sequence of the larger band (top) and exon 26 skipping, both from individual 4 (bottom) (b)

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