TXNDC15

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0030819

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0030819

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*TXNDC15* is located on chromosome 5 (5q31.1) at 5:134,873,770-134,901,635 and comprises 5 exons that encode a 360 amino acid protein. The gene product is *TXNDC15*, a member of the thioredoxin superfamily that functions as a thiol isomerase, facilitating disulfide bond formations and isomerization. Though most thiol isomerases reside in the endoplasmic reticulum (ER) of cells, *TXNDC15* lacks an ER retention motif, making its subcellular localization unclear. It contains an N-terminal signal peptide and a single central thioredoxin-like domain with four predicted N-glycosylation sites. The cellular role of *TXNDC15* is not well understood. Biallelic alterations in *TXNDC15* have been reported to cause autosomal recessive Meckel syndrome 14 (OMIM: #619879). The preferred disease name suggested for this disorder is ‘autosomal recessive ciliopathy-*TXNDC15*. *TXNDC15* was first reported in relation to autosomal recessive Meckel Syndrome in 2016 by Shaheen R et al., (PMID: 27894351). In this study, the authors utilized autozygosity mapping and targeted panel sequencing to identify homozygous loss of function mutations in *TXNDC15* in three individuals from unrelated families who unfortunately died shortly after birth/still birth. These probands demonstrated phenotypes including polydactyly, enlarged polycystic kidneys, occipital encephalocele, oligohydramnios, bilateral microphthalmia, and poor respiration culminating in a clinical diagnosis of Meckel Syndrome for all the affected individuals. All three families reported consanguinity. Since the first report of *TXNDC15* associated with Meckel Syndrome, three other studies have reported other biallelic variants in this gene (identified via trio exome sequencing) that cause similar Mecke l syndrome phenotypes (PMIDs: 30851085, 31411728, 38156946). So far, seven novel pathogenic *TXNDC15* variants have been reported, of which six are loss of function. The majority of the variants were found homozygously, while one study reported disease-causing compound heterozygous variants (PMID: 30851085). A total of 12 points for genetic evidence was reached. Although limited, this gene disease relationship is also supported by experimental evidence that demonstrates a functional alteration upon the loss of *TXNDC15* in cells. Knockdown of *TXNDC15* resulted in the reduction of primary cilia and incorrect localization of *TMEM167*, a transition zone protein (the loss of which is also associated with a ciliopathy) (PMID: 27894351). A total of 0.5 points was awarded for experimental evidence. In summary, there is Strong evidence supporting the relationship between *TXNDC15* and autosomal recessive ciliopathy-*TXNDC15*. 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 Kidney Cystic and Ciliopathy Disorders Expert Panel GCEP on the meeting date 09/25/2024 (SOP Version 11).