Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function <i>ZEB1</i> Alleles

• Main Authors: Lubica Dudakova, Viktor Stranecky, Lenka Piherova, Tomas Palecek, Nikolas Pontikos, Stanislav Kmoch, Pavlina Skalicka, Manuela Vaneckova, Alice E. Davidson, Petra Liskova
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Genes
• Subjects: <i>ZEB1</i>; cornea; penetrance; loss-of-function
• Online Access: https://www.mdpi.com/2073-4425/12/5/677

<i>ZEB1</i> loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder—posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (<i>n</i> = 3616) and genomes (<i>n</i> = 88) for the presence of putative heterozygous LoF variants in <i>ZEB1</i>. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in <i>ZEB1</i> (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (<i>n</i> = 141,456 subjects) was also interrogated for LoF <i>ZEB1</i> variants, notably 8 distinct heterozygous changes presumed to lead to <i>ZEB1</i> haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, <i>ZEB1</i> LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of <i>ZEB1</i> LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.