PAX1 – Otofaciocervical syndrome type 2

Otofaciocervical syndrome type 2 (OTFCS2) is an autosomal recessive disorder characterized by facial dysmorphism, short stature, external ear anomalies with conductive hearing loss, branchial defects, vertebral segmentation anomalies, and T-cell immunodeficiency. Biallelic loss-of-function variants in PAX1 underlie OTFCS2, manifesting with thymic hypoplasia or aplasia and consequent severe combined immunodeficiency in affected individuals.

Genetic evidence is robust: homozygous or compound heterozygous PAX1 variants have been reported in at least 17 probands across five unrelated families, including consanguineous kindreds with multiple affected siblings, segregating in an autosomal recessive pattern (PMID:35595062; PMID:32111619). One recurrent missense change, c.439G>C (p.Val147Leu), disrupts the paired-box domain and abolishes normal transcriptional activity (PMID:32111619).

The variant spectrum includes missense, small in-frame deletions (e.g., c.463_465del (p.Asn155del)), and premature truncation alleles (e.g., c.158C>A (p.Ser53Ter)), all predicted or shown to result in loss of PAX1 function. No founder variants have been established; cases arise in diverse populations.

Functional assays demonstrate that OTFCS2-associated PAX1 mutants have reduced DNA binding and transcriptional activity in luciferase reporter assays. Patient-derived induced pluripotent stem cells bearing biallelic PAX1 variants fail to differentiate into thymic epithelial progenitors and show altered transcriptional profiles of pharyngeal pouch genes, confirming pathogenicity (PMID:32111619).

Murine models further support haploinsufficiency and loss-of-function as the mechanism of disease: Pax1 null mice exhibit vertebral and sternum defects, and heterozygotes display subtle skeletal anomalies, indicating dosage sensitivity (PMID:9671740). Recent work reveals that PAX1 also represses canonical Wnt signaling during endoderm differentiation, with SCID-associated mutants unable to suppress TCF7L2 activity, thus impairing thymic epithelium development (PMID:38664733).

Integration of genetic and experimental data yields a Strong gene–disease association: multiple unrelated probands with biallelic variants, consistent autosomal recessive segregation, and concordant functional loss-of-function evidence. PAX1 testing enables rapid molecular diagnosis of OTFCS2 and guides early therapeutic interventions, including hematopoietic or thymus transplantation.

Key Take-home: Biallelic PAX1 loss-of-function variants cause autosomal recessive OTFCS2 with immunodeficiency, and functional studies confirm a haploinsufficiency mechanism essential for thymic development.

References

• European journal of medical genetics • 2022 • Dysmorphism and immunodeficiency – One of the differential diagnoses is PAX1 related otofaciocervical syndrome type 2. PMID:35595062
• Science immunology • 2020 • PAX1 is essential for development and function of the human thymus. PMID:32111619
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Targeted disruption of Pax1 defines its null phenotype and proves haploinsufficiency. PMID:9671740
• Cell communication and signaling : CCS • 2024 • PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation. PMID:38664733

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