Novel variant of TMEM231 in Meckel syndrome: a case report

A 34-year-old woman underwent routine antenatal ultrasound scanning at 17 weeks gestation which identified multiple fetal abnormalities including severe oligohydramnios, growth restriction, occipital encephalocele, short and bowed long bones, bilateral enlarged multicystic kidneys and an absent bladder. As the findings were highly suspicious for a lethal fetal ciliopathy, the patient received counselling and elected for a medical termination of pregnancy at 19 weeks. Autopsy confirmed the imaging findings, additionally demonstrating low set ears, micrognathia, a broad nasal bridge, polysyndactyly and bilateral hypoplastic lungs. A 132 gene-targeted exome-based panel revealed a novel homozygous deletion encompassing exon 1 of the tetraspanin-like transmembrane protein 231 gene (TMEM231), which encodes an essential protein of the transition zone of primary cilia. The constellation of clinical, radiological, pathological, and molecular features confirmed a diagnosis of Meckel syndrome 11 (MKS11). MKS represents a group of rare, lethal autosomal recessive syndromes caused by variations in genes encoding structural and functional proteins of primary cilia. To date, less than fifty variants in TMEM231 have been associated with phenotypes overlapping MKS, Joubert syndrome and oral-facial-digital syndrome. Our case not only highlights the valuable role of fetal autopsy for providing diagnostic information and informing genetic counselling, but also broadens the spectrum of TMEM231 variants in ciliopathies. BP contribution: original idea for case report, writing of case and performed part of autopsy.