ClinVar

In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene. All had a heterozygous 1568T-A transversion in exon 15, resulting in a val523-to-glu (V523E) substitution. The other POLR3B mutations found in compound heterozygosity with V523E were a 1508C-A transversion in exon 15, resulting in a thr503-to-lys (T503K; 614366.0006) substitution; a 1-bp deletion (1533delT; 614366.0007) predicted to result in a frameshift and premature stop codon; and a 2686A-T transversion in exon 23, resulting in a lys896-to-ter (K896X; 614366.0008) substitution. Based on electron microscopy structure, the V523E and T503K substitutions were predicted be located near the 'jaw' of pol III, where other subunits are localized. Thus these mutations would affect local structure and impair proper function of pol III. None of the mutations were found in 340 control chromosomes, except for V523E, which was found in 2 (0.5%) of 374 control chromosomes. All patients presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination.

Wolf et al. (2014) reported that 51 of 62 patients with HLD8 were compound heterozygous for the V523E variant and another mutation in the POLR3B gene. Only 1 sib pair was homozygous for V523E, and the sibs had an exceptionally mild clinical course, with the older sib having no neurologic signs at age 21 years. Brain MRI in the sibs showed much better myelination in the 2 homozygous sibs than in the other patients.

In 2 unrelated patients (patients 8 and 9) with HLD8, Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2084-6A-G transition (IVS19-6A-G; 614366.0016) in intron 19, resulting in creation of a cryptic splice site and leading to a frameshift and premature termination (Gly695ValfsTer5). The mutations were identified by sequencing of the POLR3B gene. The V523E variant had an allele frequency of 0.5% in the dbSNP database.

In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2274T-C transition resulting in a pro925-to-gln (P925Q; 614366.0015) substitution at a conserved site. The mutations were identified by Sanger sequencing of the POLR3B gene. The P925Q mutation was predicted to modify protein conformation. It was not present in the ExAC database.

In a 21-year-old Dutch Caribbean woman with HLD8, Verberne et al. (2020) identified homozygosity for the V523E mutation. The mutation was found by sequencing of a gene panel of 761 genes associated with intellectual disability. Both parents were heterozygous for the mutation. The mutation was present in the gnomAD database at an allele frequency of 0.0003%. The patient had ataxia, developmental delay, and impaired intellectual development.