Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct;60(10):1026-1034.
doi: 10.1136/jmg-2023-109223. Epub 2023 May 16.

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C

Amytice Mirchi #  1   2   3 , Simon-Pierre Guay #  4   5 , Luan T Tran  1   3 , Nicole I Wolf  6 , Adeline Vanderver  7   8 , Bernard Brais  1   4   9 , Michel Sylvain  10 , Daniela Pohl  11 , Elsa Rossignol  12 , Michael Saito  13 , Sebastien Moutton  14 , Luis González-Gutiérrez-Solana  15 , Isabelle Thiffault  16   17 , Michael C Kruer  18   19   20 , Dolores Gonzales Moron  21 , Marcelo Kauffman  22 , Cyril Goizet  23   24 , László Sztriha  25 , Emma Glamuzina  26 , Serge B Melançon  27 , Sakkubai Naidu  28 , Jean-Marc Retrouvey  29 , Suzanne Lacombe  29 , Beatriz Bernardino-Cuesta  30 , Isabelle De Bie #  4   5   31 , Geneviève Bernard #  32   2   3   4   5
Affiliations

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C

Amytice Mirchi et al. J Med Genet. 2023 Oct.

Abstract

Background: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described.

Methods: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated.

Results: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing.

Conclusion: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

Keywords: genetics; genetics, medical; neurodegenerative diseases; neurology; pediatrics.

PubMed Disclaimer

Conflict of interest statement

Competing interests: LTT currently manages sponsored clinical trials at the site level for Ionis Pharmaceuticals (Alexander disease clinical trial 2021–present), Passage Bio (Krabbe disease and GM1 gangliosidosis clinical trials, 2021–present) and Teva Pharmaceuticals (chronic and episodic migraine clinical trials, 2022–present). He also manages a GM1 gangliosidosis natural history study sponsored by the University of Pennsylvania with funding from Passage Bio. NIW is advisor and/or co-investigator for trials in Metachromatic Leukodystrophy (Shire/Takeda, Orchard, Evidera) and other leukodystrophies (Ionis, PassageBio, Vigil Neuro, Sana Biotech), without personal payment. AV receives research grants or in-kind research support without any personal compensation from Takeda, Passage Bio, Sanofi, Affynia, Orchard Therapeutics, Eli Lilly, ISD therapeutics, Illumina, Myrtelle, Homology, Sana and Ionis. She is a site investigator for the Ionis clinical trial in Alexander’s disease, SHP611 in Metachromatic leukodystrophy of Shire/Takeda and Passage Bio gene therapy in Krabbe. She serves on the scientific advisory board of the ELA foundation, the ULF Foundation and the Yaya Foundation Scientific and Clinical Advisory Council. She is a member of the Vanishing White Matter Consortium, the H-ABC Clinical Advisory Board. She receives grant funding from this RDCRN NCATS/NINDS (U01 NS106845, U54TR002823 and R21 NS123477. GB is/was a consultant for Passage Bio Inc (2020–2022) and Ionis (2019). She is/was a site investigator for the Alexander’s disease trial of Ionis (2021–present), Metachromatic leukodystrophy of Shire/Takeda (2020–2021), Krabbe and GM1 gene therapy trials of Passage Bio (2021–present), GM1 natural history study sponsored by the University of Pennsylvania with funding from Passage Bio (2021–present) and Adrenoleukodystrophy/Hematopoietic stem cell transplantation natural history study of Bluebird Bio (2019), a site sub-investigator for the MPS II gene therapy trial of Regenxbio (2021–present) and the MPS II clinical trial of Denali (2022–present). She has received an unrestricted educational grant from Takeda (2021–2022). She serves on the scientific advisory board of the Pelizaeus-Merzbacher Foundation, the Yaya Foundation Scientific and Clinical Advisory Council and is the Chair of the Medical and Scientific Advisory Board of the United Leukodystrophy Foundation. She is a member of the Vanishing White Matter Consortium, the H-ABC Clinical Advisory Board and the Chair of the POLR3-related (4H) Leukodystrophy Consortium. She is on the editorial boards of Neurology Genetics, Frontiers in Neurology – Neurogenetics and Journal of Medical Genetics.

Figures

Figure 1
Figure 1
Craniofacial characteristics in patients with POLR3-HLD by genotype. Selection of representative pictures of our patient cohort are shown. Anomaly of the lower face including a flat midface (subjects 5, 7, 9, 12, 20, 23, 27, 31), smooth philtrum (subjects 1, 9, 12, 21, 26, 27, 31) and pointed chin (subjects 1, 5, 11, 12, 21, 26, 27, 31) were among the most common craniofacial features in our cohort of patients. 1This patient also has a variant of unknown significance and a pathogenic variant in POLR3B.
Figure 2
Figure 2
Frequency of the craniofacial features described in our cohort of patients with POLR3-HLD.
See this image and copyright information in PMC

References

    1. Vanderver A, Prust M, Tonduti D, et al. . Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab 2015;114:494–500. 10.1016/j.ymgme.2015.01.006 - DOI - PMC - PubMed
    1. Soderholm HE, Chapin AB, Bayrak-Toydemir P, et al. . Elevated leukodystrophy incidence predicted from genomics databases. Pediatr Neurol 2020;111:66–9. 10.1016/j.pediatrneurol.2020.06.005 - DOI - PMC - PubMed
    1. Gordon HB, Letsou A, Bonkowsky JL. n.d. The leukodystrophies. Semin Neurol;34:312–20. 10.1055/s-0034-1386769 Available: http://www.thieme-connect.de/products/ejournals/issue/10.1055/s-004-27616 - DOI - PubMed
    1. Bernard G, Chouery E, Putorti ML, et al. . Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet 2011;89:415–23. 10.1016/j.ajhg.2011.07.014 - DOI - PMC - PubMed
    1. Tétreault M, Choquet K, Orcesi S, et al. . Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet 2011;89:652–5. 10.1016/j.ajhg.2011.10.006 - DOI - PMC - PubMed

Publication types