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A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype.

ABSTRACT: The transforming growth factor-?-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is widely expressed and participates in multiple molecular and cellular processes, including growth, differentiation, inflammation, and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and splice variants in MAP3K7 have been associated with CSCFS, whereas missense variants have been reported in both CSCFS and FMD2. Here, we present a patient with a novel heterozygous likely pathogenic variant, c.125_127del, p.(Val42del), in MAP3K7, only the sixth variant associated with CSCFS to be described in the literature. Although this patient has a phenotype that is most consistent with that of CSCFS, including valvular heart disease, short stature, fusions of the spine and bones of the hands and feet, and certain facial dysmorphisms, he interestingly has some features reported previously in FMD2 but not CSCFS. These include flexion contractures of the elbow and widely spaced first and second toes, highlighting new points of overlap between these two syndromes. We additionally point out features in the patient presented here that are rare but recurrent among CSCFS patients previously reported in the literature, as well as a new distinctive cutaneous finding not previously reported.

SUBMITTER: AbuBakr F

PROVIDER: S-EPMC7304360 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype.

AbuBakr Fatima F Jeffries Lauren L Ji Weizhen W McGrath James M JM Lakhani Saquib A SA

Cold Spring Harbor molecular case studies 20200612 3

The transforming growth factor-β-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is widely expressed and participates in multiple molecular and cellular processes, including growth, differentiation, inflammation, and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and spli ...[more]

PMID: 32299812

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Project description:SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Dataset Information

A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype.

Publications

A novel variant in <i>MAP3K7</i> associated with an expanded cardiospondylocarpofacial syndrome phenotype.

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