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

• Published in: Journal of medical genetics Vol. 60; no. 10; p. 1026
• Main Authors: Mirchi, Amytice, Guay, Simon-Pierre, Tran, Luan T, Wolf, Nicole I, Vanderver, Adeline, Brais, Bernard, Sylvain, Michel, Pohl, Daniela, Rossignol, Elsa, Saito, Michael, Moutton, Sebastien, González-Gutiérrez-Solana, Luis, Thiffault, Isabelle, Kruer, Michael C, Moron, Dolores Gonzales, Kauffman, Marcelo, Goizet, Cyril, Sztriha, László, Glamuzina, Emma, Melançon, Serge B, Naidu, Sakkubai, Retrouvey, Jean-Marc, Lacombe, Suzanne, Bernardino-Cuesta, Beatriz, De Bie, Isabelle, Bernard, Geneviève
• Format: Journal Article
• Language: English
• Published: England 01-10-2023
• Subjects: Demyelinating Diseases; DNA-Directed RNA Polymerases - genetics; Humans; Inheritance Patterns; Neurodegenerative Diseases; RNA Polymerase III - genetics; genetics, medical; neurodegenerative diseases; genetics; neurology; pediatrics
• ISSN: 1468-6244
• DOI: 10.1136/jmg-2023-109223

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