Craniofacial Features of POLR3-related Leukodystrophy Caused by Biallelic Variants in , and

Overview

Journal J Med Genet

Specialty Genetics

Date 2023 May 17

PMID 37197783

Authors

Amytice Mirchi

Simon-Pierre Guay

Luan T Tran

Nicole I Wolf

Adeline Vanderver

Bernard Brais

Michel Sylvain

Daniela Pohl

Elsa Rossignol

Michael Saito

Sebastien Moutton

Luis Gonzalez-Gutierrez-Solana

Isabelle Thiffault

Michael C Kruer

Dolores Gonzales Moron

Marcelo Kauffman

Cyril Goizet

Laszlo Sztriha

Emma Glamuzina

Serge B Melancon

Sakkubai Naidu

Jean-Marc Retrouvey

Suzanne Lacombe

Beatriz Bernardino-Cuesta

Isabelle De Bie

Genevieve Bernard

Affiliations

Soon will be listed here.

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 , , or . Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in . 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 , and 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 biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in and while a higher proportion of patients with 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 , and .

Citing Articles

Liu J, Niu Y, Qin J, Yang Z Front Neurol. 2024; 15:1355484.

PMID: 38550343 PMC: 10972892. DOI: 10.3389/fneur.2024.1355484.

Biallelic pathogenic variants in alter tRNA transcription and cause a hypomyelinating leukodystrophy: A case report.

Macintosh J, Perrier S, Pinard M, Tran L, Guerrero K, Prasad C Front Neurol. 2023; 14:1254140.

PMID: 37915380 PMC: 10616956. DOI: 10.3389/fneur.2023.1254140.

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