ARSL – X-linked Chondrodysplasia Punctata 1

X-linked chondrodysplasia punctata 1 (CDPX1; MONDO:0010555) is an X-linked recessive skeletal dysplasia caused by loss-of-function variants in ARSL (formerly ARSE) (HGNC:719). Affected males present with stippled epiphyses in infancy, nasal and midface hypoplasia, brachytelephalangy, and variable ectopic calcifications.

Genetic evidence includes 17 male probands with ARSL mutations in a multi-centre cohort ([PMID:23470839]) and 12 additional subjects in an independent series ([PMID:12567415]); three further singleton cases harboring hemizygous ARSL variants have been described ([PMID:19839041]; [PMID:20523025]; [PMID:39425194]), yielding 32 unrelated affected males. No male–male transmission is observed, consistent with X-linked recessive inheritance. Segregation is limited by small family sizes, and a maternal grandfather carrying the same deletion was asymptomatic, indicating variable penetrance ([PMID:19839041]).

The variant spectrum comprises missense (e.g. c.1258C>T (p.Arg420Trp)), nonsense, frameshift (c.1108del (p.Trp370GlyfsTer35))), splice-site, and multi-exon deletions. Recurrent alleles include c.1219G>T (p.Glu407Ter) detected in cases with severe spinal cord compression ([PMID:16937129]).

Functional studies demonstrate that missense and nonsense ARSL alleles abolish arylsulfatase E activity in COS cell assays ([PMID:12567415]; [PMID:23470839]). Prenatal WES followed by RT-qPCR, Western blot, and enzymatic assay of c.265A>G (p.Ser89Asn) confirmed loss of ARSL expression and function ([PMID:34630518]). Computational stability predictions further distinguish pathogenic from benign missense variants ([PMID:38053926]).

Integrating genetic and experimental data establishes ARSL haploinsufficiency as the mechanism underlying CDPX1. Phenotypic variability and incomplete penetrance warrant careful genetic counseling, particularly given the 50% theoretical recurrence risk for male fetuses of carrier mothers.

Key Take-home: ARSL gene testing is clinically actionable for diagnosis of X-linked chondrodysplasia punctata 1, guiding prenatal counseling and anticipatory management of skeletal and airway complications.

References

• Journal of Medical Genetics • 2012 • Genetic analyses of brachytelephalangic chondrodysplasia punctata: results from 29 male probands PMID:23470839
• American journal of medical genetics. Part A • 2003 • X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability PMID:12567415
• American journal of medical genetics. Part A • 2009 • X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple PMID:19839041
• Fetal diagnosis and therapy • 2010 • Brachytelephalangic chondrodysplasia punctata: prenatal diagnosis and postnatal outcome PMID:20523025
• BMC medical genomics • 2024 • A novel frameshift deletion variant of ARSL associated with X-linked recessive chondrodysplasia punctata 1: a case report and literature review of prenatal, confirmed cases PMID:39425194
• European journal of pediatrics • 2007 • Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases PMID:16937129
• Frontiers in genetics • 2021 • Prenatal Diagnosis in a Fetus With X-Linked Recessive Chondrodysplasia Punctata: Identification and Functional Study of a Novel Missense Mutation in ARSE PMID:34630518
• Molecular genetics and metabolism reports • 2023 • Predicting the pathogenicity of missense variants based on protein instability to support diagnosis of patients with novel variants of ARSL PMID:38053926

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