Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome

Abstract

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Keywords: POLR3A, RNA polymerase 3A; Wiedemann-Rautenstrauch syndrome; neonatal progeroid syndrome.

Figure 1

Images of Infants, Children, and Adults with Wiedemann-Rautenstrauch Syndrome and Bi-allelic POLR3A Variants Subject 1 as an infant (A) and at 17 months (B); subject 4 as an infant (C and D) and at 3 years (E); subject 5 at 3 years (F); subject 6 as an infant (G) and adult (H); and subject 7 at 5 years (I). Physical features include relative macrocephaly, a prominent forehead, a triangular-appearing face, hypertelorism, anteverted nostrils, bitemporal narrowing, upslanting palpebral fissures, thin lips, and sparse hair.

Figure 2

Physical Features of Subjects with Wiedemann-Rautenstrauch Syndrome and Bi-allelic POLR3A Variants (A) Decreased subcutaneous fat; localized fat distribution over posterior iliac region and buttocks in an infant. (B and C) Anterior (B) and posterior (C) views demonstrate marked loss of subcutaneous fat from the trunk and extremities, intact fat over the buttocks, and contractures in the hips, left elbow, and knees. (D) A lateral view demonstrates decreased subcutaneous fat in the upper and lower extremities, intact fat over the trunk, and a gastrostomy tube in the abdomen.

Figure 3

Intronic POLR3A Variants, c.3337−5T>A and c.3337−11T>C Result in Abnormal Splicing and an In-Frame Exon 26 Deletion, Resulting in p.Ile1113_Glu1143del (A) A partial gene structure for POLR3A. Exons are boxed, intronic nucleotide alterations c.3337−5T>A and c.3337−11T>C are marked, and the primer pairs used for amplification are shown as arrows above and below the exons (F = forward primer; R = reverse primer). (B) Peripheral-blood RNA samples from subject 1, her parents, and a healthy control subject demonstrate two bands (474 bp, 381 bp) for subject 1 and the mother but only one for the father and control. (C) Amplified peripheral-blood RNA samples obtained from subject 2, shown in comparison to samples from a healthy control, demonstrate two bands (243 bp, 150 bp). The dashed line indicates that the gel image has been truncated. (D and E) Gel purification, PCR, and Sanger sequencing of the two bands from subject 1 demonstrate wild-type sequence (D, larger band) and exon 26 skipping (E, smaller band). (F and G) Gel purification, PCR, and Sanger sequencing of the two bands from subject 2 demonstrate wild-type sequence (F, larger band) and exon 26 skipping (G, smaller band).