POLR3-related leukodystrophy: From exploring novel genetic causes and investigating clinical features to expanding the spectrum of disease

Leukodystrophies encompass a spectrum of inherited neurological disorders associated with central nervous system white matter abnormalities, impacting either the development or maintenance of the myelin sheath.Within this disease group, hypomyelinating leukodystrophies are characterized by a substantial lack of myelin deposition during development and are typically diagnosed using brain magnetic resonance imaging (MRI) patterns, along with molecular genetic testing.Advances in genetic sequencing technologies have facilitated the discovery of an abundance of novel genes associated with hypomyelinating leukodystrophies over recent years.Although this has led to the genetic diagnosis of many patients with rare hypomyelinating disorders, there remain a proportion of patients whose causal genes remain unidentified.Using next generation sequencing, we sought to investigate the genetic etiology of a cohort of patients presenting with hypomyelination on MRI, but without an identified genetic cause.Genetic variants for each patient were custom filtered and evaluated for pathogenicity using the American College of Medical Genetics guidelines.Genetic diagnoses were identified in 41% (7/17) of patients.In one patient, pathogenic variants in the gene POLR3K were identified, including a large deletion and a missense variant, leading to the third report worldwide of an individual harbouring pathogenic variants in this gene and a hypomyelinating phenotype.One of the most common types of hypomyelinating leukodystrophies is RNA polymerase III-related hypomyelinating leukodystrophy (POLR3-HLD).As an autosomal recessive disorder, POLR3-HLD is caused by biallelic pathogenic variants in specific genes encoding for subunits of the transcription enzyme RNA polymerase III, including POLR3A, POLR3B, POLR1C, and POLR3K.POLR3-HLD is also known as 4H leukodystrophy due to the commonly associated combination of neurological and non-neurological features, including hypomyelination, hypodontia, and hypogonadotropic hypogonadism.As endocrine and growth abnormalities are often seen in this patient population, we sought to systematically investigate and characterize these features in a large cohort of patients with genetically-confirmed POLR3-HLD.We performed an international cross-sectional study on 150 patients to evaluate endocrine and growth measures, as well as neurological and non-neurological features.Pubertal abnormalities and short stature were found to be the most common endocrine features, and thyroid abnormalities were reported in a ABSTRACT ______________________________________________________________________________ 2 portion of patients.Next, we aimed to expand the clinical and molecular spectrum of POLR3-HLD by investigating a cohort of patients with an extremely severe phenotype compared to the typical disease form.Clinical, MRI, and genetic features for all six patients were reviewed.Each had an early disease onset in the first few months of life, presenting with developmental delay, failure to thrive, and severe dysphagia.On MRI, an atypical pattern of progressive basal ganglia and thalamic abnormalities was identified.Genetically, each patient harboured similar pathogenic variants in POLR3A, including a variant leading to a premature stop codon on one allele, and in trans, a splicing variant which was investigated using in vitro studies to identify aberrant splicing transcripts.To further explore this novel phenotype, pathology samples from three deceased children of different ages were examined, revealing a progressive disease with involvement of the dorsal striatum, globus pallidus, and thalamus.Overall, the identification of genotype-phenotype correlations and study of disease progression provide insight into the complex pathophysiology underlying POLR3-HLD.As a whole, these studies expand understanding of the genetic basis, clinical presentation, and disease pathophysiology of hypomyelinating disorders, thus laying the knowledge foundation necessary for the development of future therapeutic approaches.And finally, to my friends and family near and far, I couldn't have reached the end of this degree without your constant support.To my parents, Diana and David, for being the most encouraging, loving, and supportive parents I could have ever asked for.You have shaped me into the individual I am today, and I am so thankful for your never-ending encouragement to follow my dreams.Thank you for being there through the ups and downs, and for inspiring me to put forth my best effort in everything I do.To my brothers, Michael and Christopher, my grandparents, Marlene, Zdenka, and Stefan, as well as my aunts, uncles, and cousins, you are always there for me when I need it, and I am thankful for all of your love and support.To my lifelong friends, Katie, Taylor, and Marissa, for cheering me on from the sidelines and always being in my corner.And to Dylan, we started this journey in Montral, and even from afar you have been there every step of this degree, from listening to my endless presentations to making sure I never miss an Oxford comma, and being an "extended brain" when I need to think out a new idea or plan.Your friendship is invaluable, thank you for always being there and for making me feel like my potential has no limits.To all my family and friends, I am eternally grateful for all of your love and support, you mean so much to me.

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