Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation—Family Case Report and Review of the Literature

PRKAG2 syndrome (PS) is a rare, early-onset autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), that mainly presents with ventricular pre-excitation, cardiac hypertrophy and progressive conduction system degeneration. Its natural course, treatment and prognosis are significantly different from sarcomeric HCM. The clinical phenotypes of PRKAG2 syndrome often overlap with HCM due to sarcomere protein mutations, causing this condition to be frequently misdiagnosed. The syndrome is caused by mutations in the gene encoding for the γ2 regulatory subunit (PRKAG2) of 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK), an enzyme that modulates glucose uptake and glycolysis. PRKAG2 mutations (OMIM#602743) are responsible for structural changes of AMPK, leading to an impaired myocyte glucidic uptake, and finally causing storage cardiomyopathy. We describe the clinical and investigative findings in a family with several affected members (NM_016203.4:c.905G>A or p.(Arg302Gln), heterozygous), highlighting the various phenotypes even in the same family, and the utility of genetic testing in diagnosing PS. The particularity of this family case is represented by the fact that the index patient was diagnosed at age 16 with cardiac hypertrophy and ventricular pre-excitation while his mother, by age 42, only had Wolff–Parkinson–White syndrome, without left ventricle hypertrophy. Both the grandmother and the great-grandmother underwent pacemaker implantation at a young age because of conduction abnormalities. Making the distinction between PS and sarcomeric HCM is actionable, given the early-onset of the disease, the numerous life-threatening consequences and the high rate of conduction disorders. In patients who exhibit cardiac hypertrophy coexisting with ventricular pre-excitation, genetic screening for PRKAG2 mutations should be considered

GENETIC FACTORS INVOLVED IN THE DEVELOPMENT OF CLEFT LIP AND/OR PALATE

The etiology of cleft lip (CL) and/or cleft palate (CP) has been studied in the past decade and it seems to be heterogeneous and multifactorial, with a combination of both genetic and environmental risk factors. Epidemiological surveys have shown that CL and/or CP (CL/P) are among the most frequently observed birth defects in children. The advances in the field of genetics during the past decades have led to great improvements in the early diagnosis, intervention, prophilaxy and also therapy of various genetic disorders, including those involving the abnormal development of cranio- facial structures. Fogh-Andersen (1942) provided the first population-based evidence that OC has a strong genetic component. Since then, various linkage studies have suggested numerous loci could have a causal role in CL/P. Inconsistent results could be caused by the small size of the studies or genetic heterogeneity association studies. There are many roles of the genes that are involved in oral cleft: some genes function as growth factors (eg, TGF-α, TGF-β3), transcription factors (MSX1, IRF6, TBX22), or factors that play a part in xenobiotic metabolism (CYP1A1, GSTM1, NAT2), nutrient metabolism (MTHFR, RARA) or immune response (PVRL1, IRF6). The most intensively investigated genes have been the TGF-α and MTHFR genes. Although a large number of candidate gene studies have been conducted in this field, and several genome-wide association studies (GWAS) have recently provided more clues, specific causal variants and biological mechanisms responsible for occurrence of nonsyndromic cleft lip with or without cleft palate (NSCL/P) remain unclea