Hypomyelinating Leukodystrophy 7, with or without Oligodontia and/or Hypogonadotropic Hypogonadism via the POLR3A Gene

POLR3A-related hypomyelinating leukodystrophy is a rare neurological disorder with onset between 1 and 12 years old. Major symptoms include tremor-ataxia, spasticity, cerebellar signs, upper motor neuron signs, hypodontia, delayed puberty, hypogonadotropic hypogonadism and cognitive regression. Minor features include developmental delay, seizure, peripheral neuropathy, and decreased vibratory and positional sense. Most patients become wheelchair-bound between 5 and 30 years old. MRI image analysis shows hypomyelinating leukodystrophy. The phenotype is variable (Bernard et al. 2011. PubMed ID: 21855841; Perrier et al. 2020. PubMed ID: 32582862; Harting et al. 2020. PubMed ID: 31940116).  

Pathogenic variants in POLR3A also cause another severe phenotype, Wiedemann-Rautenstrauch syndrome, which is characterized by growth retardation, sparse scalp hair, generalized lipodystrophy with characteristic local fatty tissue accumulations, and an unusual face. Onset is in utero and death can occur in early childhood (Paolacci et al. 2018. PubMed ID: 30323018).

As hypomyelinating leukodystrophy can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

POLR3A-related hypomyelinating leukodystrophy is inherited in an autosomal recessive manner. Pathogenic variants in POLR3A include missense, nonsense, splicing, small deletion/duplications, and small indel variants. Large deletions have also been reported in the POLR3A locus (Human Gene Mutation Database). De novo pathogenic variants are not common.

It has been speculated that genotypes with bi-allelic missense variants or a missense variant in trans with a splicing or truncating variant are causative for the distinct phenotype of hypomyelinating leukodystrophy, whereas bi-allelic splicing or truncating variants, or a strong spicing or truncating variant in trans with a milder hypomorphic variant (often a deep intronic variant partially affecting splicing), are associated with Wiedemann-Rautenstrauch syndrome (Wambach et al. 2018. PubMed ID: 30414627; Paolacci et al. 2018. PubMed ID: 30323018).

POLR3A encodes the largest subunit A of RNA polymerase III, which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs (Bernard et al. 2011. PubMed ID: 21855841; Wambach et al. 2018. PubMed ID: 30414627). However, a mouse model with the French Canadian founder mutation (homozygous Polr3a c.2015G > A (p.Gly672Glu)) did not show neurological abnormalities (Choquet et al. 2017. PubMed ID: 28407788). POLR3A has been cited as an essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Pathogenic variants in POLR3A are considered one of the major causes of hypomyelinating leukodystrophies. In 37 patients with hypomyelinating leukodystrophies, all had pathogenic variants either in POLR3A (27 cases) or in POLR3B (10 cases; Daoud et al. 2013. PubMed ID: 23355746, Bernard et al. 2011. PubMed ID: 21855841, Tétreault et al. 2011. PubMed ID: 22036172, Potic et al. 2012. PubMed ID: 22451160).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the POLR3A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).