New Phenotypes for Old Genes

Background and Aim : The basis of modern genetics is based on Mendelian inheritance where monogenic disorders are subdivided into dominant or recessive, depending on whether one copy or both copies of the gene need to be mutated for the disease or condition to manifest. Methods Here we give examples of three different genes that are known to cause an autosomal dominant condition and are giving a completely different phenotype when both copies of the gene are mutated. Results In humans heterozygous loss of function TBX4 mutations cause dominant Small Patella Syndrome (SPS) due to haploinsufficiency. Here, we characterize a novel clinical entity in two fetus with complete Posterior Amelia with Pelvis and Pulmonary hypoplasiA. (GLI3) has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. GLI3 variants are associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (MIM #146510), Postaxial polydactyly types A1 and B (MIM #174200), Preaxial polydactyly type 4 (MIM #174700) and Hypothalamic hamartomas (MIM 241800). All disorders are all transmitted in an autosomal dominant manner. Here we report a related couple with Postaxial polydactyly type A1 (PAPA1) in the father and Postaxial polydactyly type B (PAPB) in the mother, with a fetus with clinical features most compatible with Pallister-Hall syndrome. TOR1A, encoding the protein TorsinA, is associated with isolated early-onset dystonia (termed DYT1-dystonia). In 2017 we reported four children from three families with homozygote variants in TOR1A with severe psychomotor retardation, strabismus, arthrogryposis and tremor. The phenotype is completely different from what we observe in heterozygote TOR1A patients. Conclusion However in recent years we are coming across cases that do not follow this rule showing us the complexity of monogenic disorders. We are seeing that mutations in the same gene may follow dominant or recessive in some families. Methods : Here we give examples of three different genes that are known to cause an autosomal dominant condition and are giving a completely different phenotype when both copies of the gene are mutated.Results : Results In humans heterozygous loss of function TBX4 mutations cause dominant Small Patella Syndrome (SPS) due to haploinsufficiency. Here, we characterize a novel clinical entity in two fetus with complete Posterior Amelia with Pelvis and Pulmonary hypoplasiA. Conclusion : However in recent years we are coming across cases that do not follow this rule showing us the complexity of monogenic disorders. We are seeing that mutations in the same gene may follow dominant or recessive in some families.

Keywords:

dominant , homozygote , heterozygote , GLI3 , TBX4 , TOR1A