A prenatally diagnosed case of Meckel–Gruber syndrome with novel compound heterozygous pathogenic variants in the TXNDC15 gene

Abstract

Background Meckel–Gruber syndrome (MKS) is a well‐known rare disease that can be detected on prenatal ultrasound. Meckel–Gruber syndrome has very heterogeneous etiology; at least, 17 genes have been described in association with MKS. The characteristic findings in fetuses affected by MKS are encephalocele (usually occipital), postaxial polydactyly, and polycystic dysplastic kidneys. However, the association of the TXNDC15 gene with MKS has been reported only once before in three consanguineous families. Methods We report a new case of MKS diagnosed at 12 + 1 weeks of gestation with typical ultrasound findings, but with novel compound heterozygous pathogenic variants in the TXNDC15 gene identified by whole‐exome sequencing (WES). Results This is the second clinical report supporting TXNDC15 as a novel causative gene of MKS, and the first describing a case in a non‐consanguineous family with causative compound heterozygous mutations. Conclusions Meckel–Gruber syndrome is a very heterogeneous syndrome in terms of the associated causal genes. In the first‐line diagnosis, we used an next‐generation sequencing (NGS)‐based large gene panel, but only 10 MKS genes were available on the platform used. In the case of prenatal ultrasound findings that are highly suggestive of MKS and a negative NGS MKS gene panel, WES should also be performed to not miss rare gene associations.

Meckel syndrome: Clinical and mutation profile in six fetuses

“…In addition to the polydactyly, we (Table S3). 16 (Table S3). The pathogenic variants in TXNDC15 cause aberrant localization of TMEM67 to the transition zone, reduced number of ciliated cells and abnormal ciliary morphology.…”

“…TXNDC15 : Thioredoxin Domain‐containing protein 15, encodes a protein thioredoxin fold which intricate in disulfide isomerase activity. Two reports have implicated TXNDC15 in MKS earlier . Shaheen et al, identified two homozygous variants [c.672_686del, c.103 + 1G > A, c.956dup] in TXNDC15 , in three unrelated fetuses with classical features of MKS for the first time .…”

“…Recently, a clinical report has been published with the variant c.(211dup/635 T > C) in TXNDC15 as a cause of MKS in a 12‐weeks‐fetus from an Estonian family (Table S3). Here, we describe an additional family with a novel homozygous variant c.844C > T, p.(Arg282Ter) in TXNDC15 as a cause of MKS in a fetus (family 1). Overall, five pathogenic variants have been reported in TXNDC15 previously in fetuses with MKS.…”

Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5

“…Mutations in TMX5 gene have recently been associated with the development of the Meckel-Gruber syndrome (MKS), a rare perinatally lethal autosomal recessive disease caused by defective ciliogenesis [ 58 ]. Deletions and missense mutations result in the generation of truncated forms of TMX5 that do not localize within primary cilium or periciliary regions as the wild type [ 59 , 60 , 61 ]. Thus, the mis-localization or the premature degradation of TMX5 might correlate with the onset of such ciliopathies.…”

Síndrome Meckel-Gruber: diagnóstico prenatal. Reporte de un caso en el sureste de México

“…Su incidencia es variable, depende de la región geográfica y del origen étnico. 4,5 www.medigraphic.org.mx…”