Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform-specific N-terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN-VI and suggest a central role for cell-motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes. K E Y W O R D S BPAG1, bullous pemphigoid antigen 1, cell adhesion, cell migration, cytoskeleton, dermal fibroblasts, DST, dystonin, hereditary sensory and autonomic neuropathies, HSAN 106

Myocd ΔLZ mice complied with federal and institutional guidelines and were reviewed and approved by the UCSF IACUC. The Mgb mouse studies were approved by the IACUC of the Nationwide Children's Hospital.

Objective:To describe the clinical and genetic findings in a cohort of subjects with bathing epilepsy, a rare form of reflex epilepsy.Methods:We investigated by Sanger and targeted re-sequencing the SYN1 gene in 12 individuals from 10 different families presenting with seizures primarily triggered by bathing or showering. Additional twelve subjects with hot-water epilepsy were also screened.Results:In all families with bathing epilepsy we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in SYN1, nine of which are novel. Conversely, none of the subjects with hot-water epilepsy displayed SYN1 variants. In mutated subjects, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail-clipping, hair-cutting, or watching someone take a shower. Non-provoked seizures and a variable degree of developmental delay were also common.Conclusion:bathing epilepsy is genetically distinct reflex epilepsy mainly caused by SYN1 mutations.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca 2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11related THS.