Expanding the Genotypic and Phenotypic Spectrum of OFD1-Related Conditions: Three More Cases

Pathogenic variants in the OFD1 gene are linked to a spectrum of syndromes that exhibit partial clinical overlap. Hemizygous loss-of-function variants are considered lethal in males, while heterozygous loss-of-function variants generally result in oro-facial-digital syndrome type 1. A reported phenotype, Simpson-Golabi-Behmel syndrome type 2, was published once but remains controversial, with many specialists questioning its validity and arguing about its continued listing in the OMIM database.

To investigate the genetic and phenotypic characteristics of the patients, we performed clinical exome sequencing, family-based genetic analysis, X-inactivation studies, electron microscopy, and detailed clinical assessments.

Three patients from unrelated families carrying loss-of-function variants in the OFD1 gene were identified, emphasizing the diverse phenotypic spectrum of OFD1-associated disorders. The first patient, a female with a heterozygous frameshift variant p.(Gln398LeufsTer2), was diagnosed with oro-facial-digital syndrome type 1. The second patient, a male with a heterozygous nonsense variant p.(Gln892Ter), presented with features resembling Simpson-Golabi-Behmel syndrome type 2, as previously reported under this diagnosis. The third patient, a male with another heterozygous nonsense variant p.(Glu879Ter), exhibited isolated primary ciliary dyskinesia without any syndromic features.

This study contributes to the growing body of evidence on the expanding phenotypic spectrum of OFD1-associated disorders. It underscores the need for further investigation into the molecular mechanisms underlying the diverse presentations and the necessity of re-evaluating diagnostic classifications for conditions such as SGBS2 in the context of variants in the OFD1 gene.