ARSL

Inheritance Pattern: XL

Disease ID:MONDO:0010555

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010555

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010555

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010555

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010555

Submitter: ClinGen

ARSL was first reported in relation to X-linked chondrodysplasia punctata (CDPX), a rare disorder affecting bone and cartilage, in 1976 (Sheffield et al., 1976 PMID 993917) . At least 40 unique variants (missense, nonsense, small deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 50 probands in seven publications. Variants were found to be maternally inherited in all of the cases where mothers of male probands were tested. There was also evidence of segregation in at least three families, where the variant was identified in other family members with similar features (Sheffield et al. 1998 PMID 9863597; Nino et al., 2008 PMID 18348268; Garnier et al., 2007 PMID 16937129). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for CDPX1 is haploinsufficiency. This gene-disease relationship is supported by relevant experimental evidence showing that the biochemical function of ARSL deficiency resulting in CPDX is similar to the phenotype of warfarin embryopathy (Franco et al., 1995 PMID 7720070). Functional alteration resulting in deficiency of heat-labile arylsulfastase activity was shown in CPDX patient cells (Franco et al., 1995 PMID 7720070). In summary, ARSL is definitively associated with X-linked chondrodysplasia punctata. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on 7.28.2020 (SOP Version 7). From the Prenatal GCEP's secondary review on August 29th, 2023: In addition to the previous primary curation, there is also clear prenatal/neonatal phenotype associated with ARSL and X-Linked Chondrodysplasia Punctata, evident in many probands demonstrating the gene-disease association, and biochemical function and functional alteration of patient cells evidence. Common ultrasound findings include polyhydramnios, nasal hypoplasia, and calcification or stippling of bones, while radiograph findings include vertebral calcifications.