Non‐syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X‐linked recessive manner

Abstract

Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high‐throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non‐syndromic A/M. Whole exome‐sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A>G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X‐linked recessive pattern of inheritance. This is the first report of X‐linked recessive non‐syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X‐linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.

Structural model of human PORCN illuminates disease-associated variants and drug-binding sites

“…However, male patients with PORCN mutations who do not display typical FDH symptoms have been reported (Brady et al, 2015;Madan et al, 2017;Wawrocka et al, 2021). In particular, one family of brothers (hemizygous Y245C) had anophthalmia/microphthalmia (Wawrocka et al, 2021), which is not typically seen in FDH patients. We analyzed two such mutations, Y245C (possibly damaging) and S250F (probably damaging) by Polyphen-2 (Madan et al, 2017).…”

“…FDH is usually found in heterozygous females where the severity of the disease depends on the pattern of X-inactivation or the presence of somatic mosaicism. Males may also have FDH, usually in the setting of a mosaic mutation, although germline mutations in PORCN have been identified in hemizygous males with colobomata, microphthalmia, anophthalmia or other findings of FDH (Brady et al, 2015;Madan et al, 2017;Wawrocka et al, 2021).…”

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study

“…ID has been reported in 15% of patients. 38 Although the X-linked dominant inheritance pattern has associated the PORCN gene with this particular ontology, we suggest that the "ID" ontology should be added to its coverage due to being a relatively common and significant clinical finding.…”

Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum

“…Patient 7 presented a heterozygous variant in the PORCN gene that could be related with his MAC phenotype, based on a report of a family with male individuals with variants in PORCN and presenting with isolated microphthalmia [30].…”