Hypomyelinating Leukodystrophy 8 with or without Oligodontia and/or Hypogonadotropic Hypogonadism via the POLR3B Gene

POLR3B-related hypomyelinating leukodystrophy is a rare neurological disorder characterized by deficient cerebral myelin formation and cerebellar atrophy with onset between 2 and 4 years old. This disorder was also known as 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy. The major symptoms include gross motor delay or regression before six years old, short stature, tremor-ataxia, spasticity, cerebellar atrophy, unsteady, wide-based gait, myopia, and mild to moderate intellectual disability. Minor features include dysphagia, hypodontia, oligodontia, and hypogonadotropic hypogonadism. MRI image analysis shows diffused hypomyelination and thin corpus callosum.  Phenotype is variable, slowly progressive or nonprogressive (Tétreault et al. 2011. PubMed ID: 22036172; Wolf et al. 2014. PubMed ID: 25339210).  

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.

POLR3B-related hypomyelinating leukodystrophy is inherited in an autosomal recessive manner. Pathogenic variants in POLR3B include missense, nonsense, splicing, and small deletions. Large deletions have also been reported in the POLR3B locus (Human Gene Mutation Database). De novo pathogenic variants are not common.

POLR3B encodes the second largest subunit B of RNA polymerase III, which is responsible for the transcription of transfer RNAs (tRNAs) and a large array of other small non-coding RNAs (Tétreault et al. 2011. PubMed ID: 22036172). A mouse model with a homozygous Polr3b c.308G > A (p.Arg103His) variant resulted in embryonic lethality and malfunction of RNA polymerase III biogenesis (Choquet et al. 2019. PubMed ID: 31221184). POLR3B is relatively intolerant to missense variants (Genome Aggregation Database). POLR3B has been cited as an essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Pathogenic variants in POLR3B 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 POLR3B 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).