Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy.

Congenital heart defects (CHD) are the most frequent type of congenital anomaly and are often associated with genetic and chromosomal syndromes. Haploinsufficiency of TAB2 (TGF-beta activated kinase 1/MAP3K7 binding protein 2) has been proposed to cause valvular and cardiac outflow tract structural abnormalities. In this study, we describe 13 newly identified individuals with microdeletions of chromosome 6q25.1 that involve TAB2. One of the patients in our study cohort has the smallest deletion yet reported, affecting only TAB2. These were compared to 27 other patients reported in the published literature or DECIPHER to have similar microdeletions, for a total study group of 40 patients. Our study shows that individuals with TAB2 deletions are predisposed to developing a primary cardiomyopathy with reduced systolic function, even in the absence of CHD. Our study cohort also shares a number of non-cardiac phenotypic findings: characteristic dysmorphic facial features, intrauterine growth restriction and/or postnatal proportionate short stature, hypotonia, developmental delay and/or intellectual disability, and connective tissue abnormalities. We conclude that a microdeletion of 6q25.1 that includes TAB2 causes a distinctive, multi-systemic syndrome. The 6q25.1 microdeletion syndrome should be considered in a patient with cardiomyopathy or a CHD, especially valve and/or atrial or ventricular septal abnormalities, and with phenotypic features described in this study. We recommend that patients with a TAB2 deletion be screened longitudinally for systolic heart failure, even if an initial echocardiogram is normal.

Ehlers-Danlos syndrome hypermobility type is associated with rheumatic diseases.

We retrospectively analyzed electronic medical records of patients with Ehlers-Danlos Syndrome hypermobility type (HEDS), including demographic information, workup, rheumatological diagnoses in order to determine its association with rheumatological conditions. HEDS Patients were stratified according to level of workup received (no additional work (physical exam only) = NWU, limited workup = LWU, comprehensive workup = CWU)). HEDS patients were predominantly female (21:4, F:M). The percentage of patients with at least one rheumatological condition was significantly correlated with level of workup (NWU, 9.2%; LWU, 33.3%, CWU, 67.1%; p-value < 0.0001). The HLA-B27 antigen was more prevalent (p-value < 2.2 × 10-8) in the CWU HEDS patients (23.9%) than in the general population of the United States (6.1%). HEDS with CWU were associated with more rheumatological conditions (i.e. psoriasis, ankylosing spondylitis, rheumatoid arthritis, fibromyalgia) than those with NWU or LWU. In conclusion, HEDS is associated with complicated rheumatological conditions, which are uncovered by comprehensive workup. These conditions require different clinical management strategies than HEDS, and left untreated could contribute to the pain or even physical disability (i.e. joint erosions) in HEDS patients. While the mechanisms underlying these associations are unknown, it is important that all HEDS patients receive adequate workup to ensure a complete clinical understanding for the best care strategy possible.

A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.

The proteins encoded by TELO2, TTI1, and TTI2 interact to form the TTT complex, a co-chaperone for maturation of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Here we report six affected individuals from four families with intellectual disability (ID) and neurological and other congenital abnormalities associated with compound heterozygous variants in TELO2. Although their fibroblasts showed reduced steady-state levels of TELO2 and the other components of the TTT complex, PIKK functions were normal in cellular assays. Our results suggest that these TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of ID.