RIPK4 – Bartsocas-Papas Syndrome

This summary outlines the strong association between mutations in RIPK4 and Bartsocas-Papas syndrome. Multiple independent case reports and multi‐patient studies have identified numerous homozygous and compound heterozygous variants in RIPK4 that segregate with the disease in autosomal recessive families ([PMID:23610050]). The clinical presentations include dysmorphic features of the ectoderm such as sparse hair, nail dysplasia, hypohidrosis, and ankyloblepharon, forming a distinct syndromic phenotype that expands the traditional boundaries of Bartsocas-Papas syndrome.

Genetic evidence supporting this association is robust. In several studies, pathogenic variants – including missense and loss‑of‑function changes – were identified in affected probands; for example, the variant c.488G>A (p.Gly163Asp) was reported in one case and is representative of the molecular changes observed ([PMID:26129644]). Segregation analyses in consanguineous pedigrees have documented additional affected relatives sharing the variant ([PMID:26129644]), reinforcing the genetic link.

Case series and multi‐patient studies have consistently reported a spectrum of RIPK4 mutations across independent families. Besides c.488G>A (p.Gly163Asp), other pathogenic changes—such as c.850G>A (p.Glu284Lys) and frameshift variants—have been documented. These studies collectively include approximately 20 probands from multiple families ([PMID:23610050]), providing compelling genetic evidence and reaching ClinGen scoring limits in support of the gene–disease association.

Functional studies further substantiate the pathogenicity of RIPK4 variants. Experimental work has demonstrated that mutations disrupt the serine/threonine kinase activity of RIPK4, impair IRF6 activation, and ultimately affect keratinocyte differentiation. In vitro kinase assays and molecular modeling experiments have shown that these disruptions align with the observed clinical phenotype ([PMID:25246526], [PMID:22197489]).

There remains some phenotypic variability and overlap with related syndromes such as CHAND syndrome, suggesting that mutation location within or adjacent to the kinase domain may modulate severity. However, the preponderance of evidence consistently indicates that RIPK4 alterations are central to the pathogenesis of Bartsocas-Papas syndrome with autosomal recessive inheritance.

In conclusion, the integration of extensive genetic data with supportive functional studies establishes a strong association between RIPK4 and Bartsocas-Papas syndrome. This association has significant clinical utility, driving diagnostic decision‑making and informing recurrence risk counseling.

References

• American journal of medical genetics. Part A • 2013 • Exome analysis in clinical practice: expanding the phenotype of Bartsocas-Papas syndrome PMID:23610050
• American journal of medical genetics. Part A • 2015 • Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes PMID:26129644
• American journal of human genetics • 2012 • Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome PMID:22197489
• The Journal of biological chemistry • 2014 • Receptor-interacting protein kinase 4 and interferon regulatory factor 6 function as a signaling axis to regulate keratinocyte differentiation PMID:25246526
• American journal of medical genetics. Part A • 2017 • Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome PMID:28940926

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