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FAM111A (family with sequence similarity 111 member A) is a serine protease and removes covalent DNA-protein cross-links during DNA replication. Heterozygous gain-of-function variants in FAM111Acause skeletal dysplasias, such as the perinatal lethal osteocraniostenosis and the milder Kenny-Caffey syndrome (KCS). We report two siblings born to consanguineous parents with dysmorphic craniofacial features, postnatal growth retardation, ophthalmologic manifestations, hair and nail anomalies, and skeletal abnormalities such as thickened cortex and stenosis of the medullary cavity of the long bones suggestive of KCS. Using exome sequencing, a homozygous synonymous FAM111Avariant, NM_001312909.2:c.81 G > A; p.Pro27=, that affects the last base of the exon and is predicted to alter FAM111Apre-mRNA splicing, was identified in both siblings. We identified aberrantly spliced FAM111Atranscripts, reduced FAM111AmRNA levels, and near-complete absence of FAM111A protein in fibroblasts of both patients. After treatment of patient and control fibroblasts with different concentrations of camptothecin that induces covalent DNA-protein cross-links, we observed a tendency towards a reduced proportion of metabolically active cells in patient compared to control fibroblasts. However, under these culture conditions, we did not find consistent and statistically significant differences in cell cycle progression and apoptotic cell death between patient and control cells. Our findings show that FAM111A deficiency underlies an autosomal recessive form of FAM111A-related KCS. Based on our results and published data, we hypothesize that loss of FAM111A and FAM111A protease hyperactivity, as observed for gain-of-function patient-variant proteins, may converge on a similar pathomechanism underlying skeletal dysplasias.

VLDLRcerebellar hypoplasia is characterized by intellectual disability, non-progressive cerebellar ataxia, and seizures. The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem. Biallelic VLDLRpathogenic variants cause loss-of-function of the encoded very low-density lipoprotein receptor. VLDLRexons 4 and 16 are alternatively spliced, resulting in the expression of four transcript variants, including two exon 4-lacking mRNAs expressed in the human brain. Previously reported VLDLRpathogenic variants affect all four transcript variants. Here we report on two sisters with facial dysmorphism, microcephaly, intellectual disability, and normal brain imaging. Exome sequencing in one patient identified the homozygous VLDLRnonsense variant c.376C>T; p.(Gln126*) in exon 4; her similarly affected sister also carried the homozygous variant and parents were heterozygous carriers. VLDLRtranscript analysis identified mRNAs with and without exon 4 in patient fibroblasts, while exon 4-containing VLDLRmRNAs were predominantly detected in control fibroblasts. We found significantly reduced VLDLRmRNA levels in patient compared to control cells, likely caused by nonsense-mediated mRNA decay of exon 4-containing VLDLRtranscripts. Expression of neuronal VLDLR isoforms produced from exon 4-lacking transcripts may have protected both patients from developing the cerebellar hypoplasia phenotype.