RESUMEN
Recent advancements in genetic testing have revealed cases of mosaicism, demonstrating the phenomenon may be more common than once thought. Broadly defined, mosaicism describes the presence of two genotypically different cell lineages within the same organism. This can arise from small mutations or errors in chromosome segregation, as early as in gametes, before or after fertilization. Mosaicism is directly responsible for many conditions that present in a wide range of tissues, with the presence of the mutation or genetic abnormality following a tissue-dependent pattern. This makes it possible for patients to test negative for a condition using a standard tissue sample while harboring the variant in a different tissue. Understanding the timing and mechanisms of mosaic conditions will aid in targeted testing that is more appropriate to identify a pathogenic variant. This targeted testing should reduce the length of a patient's diagnostic odyssey and provide a better understanding of the chances of passing on their variant to their offspring, thereby allowing for more accurate genetic counseling. We illustrate this phenomenon with two cases: one of Pallister-Killian syndrome and the other of tuberous sclerosis complex. Both patients had increased time to diagnosis because of difficulties in identifying genetic variants in tested tissues. Beyond just increased time to diagnosis, we illustrate that mosaic conditions can present as less severe and more variable than the germline condition and how specific germ layers may be affected by the variant. Knowing which germ layers may be affected by the variant can give clinicians a clue as to which tissues may need to be tested to yield the most accurate result.
RESUMEN
PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
