Kenny-Caffey Syndrome Type 2 via the FAM111A Gene

Kenny-Caffey syndrome is classified into two types in terms of clinical phenotypes and corresponding genetic defects. Kenny-Caffey syndrome Type 2 is an autosomal dominant disorder characterized by impaired skeletal development (tiny bones with constricted medullary cavities, dysfunction of the cranial sutures, defective dentition and microphthalmia) and primary hypoparathyroidism with hypocalcemia (Unger et al. 2013). Osteocraniostenosis (OCS; also known as gracile bone dysplasia) is the allelic disorder of Kenny-Caffey syndrome Type 2, and is a perinatally lethal condition. Compared with Kenny-Caffey syndrome Type 1, Kenny-Caffey syndrome Type 2 and OCS present normal mentality, but commonly have ophthalmologic features (corneal and retinal calcifications and congenital cataracts).

Kenny-Caffey syndrome Type 2 is an autosomal dominant disorder caused by FAM111A variants (Unger et al. 2013). The FAM111A gene (2 coding exons) encodes a cell-cycle regulated protein which is crucial to parathyroid hormone production, calcium homeostasis, and skeletal development. FAM111A variants also cause OCS. Known FAM111A pathogenic variants are clustered at the C-terminal of the encoded protein. Genetic defects documented to date in FAM111A include mostly missense variants and a small in-frame deletion (Human Gene Mutation Database).

The mutation detection rate of FAM111A in a large cohort of patients with Kenny-Caffey syndrome Type 2 is unknown in the literature because mutations have been reported only in limited cases. Analytical sensitivity should be high as the reported pathogenic variants are detectable by sequencing.

No large deletions or duplications have been reported to date in FAM111A.

This test provides full coverage of all coding exons of the FAM111A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).