Popliteal Pterygium Syndrome 2, Lethal Type via the RIPK4 Gene

Popliteal pterygium syndrome 2, lethal type (also called Bartsocas-Papas syndrome, or multiple pterygium syndrome, ASLAN type) is featured by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Other clinical features may include clubfeet, nail hypoplasia, genital anomalies, flexion contractures and arthrogryposis of joints, cutis aplasia, widely spaced nipples, low-set umbilicus, and unilateral renal hypoplasia. Early death is common; however, some patients have survived into childhood (Mitchell et al. 2012). In addition to popliteal pterygium syndrome, defects in RIPK4 also cause autism spectrum disorder (Bi et al. 2012). A homozygous RIPK4 mutation was also identified in a patient affected with Hay-Wells like syndrome presenting with ankyloblepharon-ectodermal defects-cleft lip/palate (Gripp et al. 2013).

Popliteal pterygium syndrome 2, lethal type is an autosomal recessive disorder caused by mutations in the RIPK4 gene. The RIPK4 protein (Receptor-interacting protein kinase, also called RIP4) coded by the RIPK4 gene belongs to a RIP kinase family of serine/threonine protein kinases that regulate NF-kb and JNK function. RIPK4 contains an N-terminal RIP-like kinase motif, a Ser/Thr- rich domain, and a C-terminal 11 ankyrin repeats. Studies suggested that RIPK4 serves as a target of TP63 and is required for epidermal development (Meylan et al. 2002). To date, only 7 unique pathogenic mutations have been identified. They are: 5 missense, 1 nonsense and 1 small duplication (Human Gene Mutation Database; Kalay et al. 2012; Mitchell et al. 2012, Bi et al. 2012 and Gripp et al. 2013). No large deletions and duplications have been reported.

Due to limited publications, clinical sensitivity is currently unknown. The mutation detection rate by sequencing should be high, because only seven unique RIPK4 pathogenic variants have been reported. They all are point mutations and can be detected by sequencing (Human Gene Mutation Database; Kalay et al. 2012; Mitchell et al. 2012, Bi et al. 2012 and Gripp et al. 2013).

No large deletions or duplications have been reported to date in the RIPK4 gene (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the RIPK4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).