Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

Cockayne syndrome is an ultra-rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6) mutations account for most cases. We report a child with pre- and post-natal growth failure and progressive neurologic deterioration with multi-system involvement who has bi-allelic ERCC6 variants, that were discovered by whole genome sequencing, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation. The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify non-coding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.