Biallelic PAX1 germline loss-of-function (LOF) variants were first reported in association to otofaciocervical syndrome type 2 (OTFCS2), with other groups later identifying a subset of patients with severe combined immunodeficiency (SCID) (PMID: 32111619, 28657137, 29681087). OTFCS2 is characterized by facial dysmorphism, external ear anomalies with preauricular pits, hearing impairment, hypoparathyroidism, anomalies of the vertebrae and shoulder, and mild intellectual disability. OTFCS2 patients that present with SCID demonstrate thymic aplasia/hypoplasia and T-B+NK+ SCID. 13 variants were curated and are composed of missense, nonsense and frameshift mutations. Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have been identified that show full penetrance of the OTFCS2 phenotype with variable expressivity without signs of immunodeficiency, though the immune system has not been extensively studied in these patients (PMID: 35879406). The maximum score for genetic evidence has been reached for this curation (12 pts).
PAX1 is a member of the paired box-containing (PAX) family of transcription factors and plays a role in pattern formation during embryogenesis. It is primarily expressed in the third pharyngeal pouch that generates the thymus, thyroid, parathyroid and middle ear during human development (PMID: 36393845). PAX1 is essential for the development of the thymus, is expressed in thymic epithelial cells during embryogenesis and into adulthood (PMID:2453291). Mice with different LOF mutations in PAX1 demonstrate impacts in the cellularity of the thymus as well as thymocyte development and maturation (PMID:8565834). This is most likely due to the impact of PAX1 on thymic epithelial cells, as cell culture model systems have shown altered thymic stromal cell transcriptomes following induced pluripotent stem cell differentiation (PMID: 32111619). In patients with OTFCS2, thymic transplant has shown promise in patients presenting with immunodeficiency, while HSCT has been less successful (PMID: 37060484, 33987750). Not all reports of OTFCS2 have reported patients with SCID phenotypes. It is currently unclear if this is due to reduced penetrance, the type or location of the mutation in PAX1 or other genetic modifiers. Further study is required to elucidate this finding.
In summary, there is definitive evidence to support this gene-disease relationship. This association 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 SCID-CID Working Group on 11/16/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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