Dental Phenotype with Minor Ectodermal Symptoms Suggestive of WNT10A Deficiency.

Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders characterized by the abnormal development of ectodermal-derived tissues. They include the involvement of the hair, nails, skin, sweat glands, and teeth. Pathogenic variants in EDA1 (Xq12-13.1; OMIM*300451), EDAR (2q11-q13; OMIM*604095), EDARADD (1q42-q43, OMIM*606603), and WNT10A (2q35; OMIM*606268) genes are responsible for most EDs. Bi-allelic pathogenic variants of WNT10A have been associated with autosomal recessive forms of ED, as well as non-syndromic tooth agenesis (NSTA). The potential phenotypic impact of associated modifier mutations in other ectodysplasin pathway genes has also been pointed out. We present on an 11-year-old Chinese boy with oligodontia, with conical-shaped teeth as the main phenotype, and other very mild ED signs. The genetic study identified the pathogenic variants WNT10A (NM_025216.3): c.310C > T; p. (Arg104Cys) and c.742C > T; p. (Arg248Ter) in compound heterozygosis, confirmed by parental segregation. In addition, the patient had the polymorphism EDAR (NM_022336.4): c.1109T > C, p. (Val370Ala) in homozygosis, named EDAR370. A prominent dental phenotype with minor ectodermal symptoms is very suggestive of WNT10A mutations. In this case, the EDAR370A allele might also attenuate the severity of other ED signs.

Homozygous Pro1066Arg MYBPC3 Pathogenic Variant in a 26Mb Region of Homozygosity Associated with Severe Hypertrophic Cardiomyopathy in a Patient of an Apparent Non-Consanguineous Family.

MYPBC3 and MYH7 are the most frequently mutated genes in patients with hereditary HCM. Homozygous and compound heterozygous genotypes generate the most severe phenotypes. A 35-year-old woman who was a homozygous carrier of the p.(Pro1066Arg) variant in the MYBPC3 gene, developed HCM phenocopy associated with left ventricular noncompaction and various degrees of conduction disease. Her father, a double heterozygote for this variant in MYBPC3 combined with the variant p.(Gly1931Cys) in the MYH7 gene, was affected by HCM. The variant in MYBPC3 in the heterozygosis-produced phenotype was neither in the mother nor in her only sister. Familial segregation analysis showed that the homozygous genotype p.(Pro1066Arg) was located in a region of 26 Mb loss of heterozygosity due to some consanguinity in the parents. These findings describe the pathogenicity of this variant, supporting the hypothesis of cumulative variants in cardiomyopathies, as well as the modulatory effect of the phenotype by other genes such as MYH7. Advancing HPO phenotyping promoted by the Human Phenotype Ontology, the gene-disease correlation, and vice versa, is evidence for the phenotypic heterogeneity of familial heart disease. The progressive establishment of phenotypic characteristics over time also complicates the clinical description.