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For more than a quarter century now, gene manipulation in different model systems have dominated the loss-
and gain-of-function molecular studies. Non-mendelian phenomena such as penetrance and expressivity however could
often produce a genotype-phenotype gap, resulting in flawed interpretations and hypothetical models. In general,
complexity of traits and redundancy of genetic functions are invoked to explain these discrepancies. I will describe our
experiences with a monogenic condition called microcephaly with pontine and cerebellar hypoplasia (MICPCH), which
associates with mutations in an X-linked gene, CASK. CASK is an essential gene with no other known genetic isoforms.
On basis of case-studies, animal model experiments and molecular studies we suggest, that the nature of mutations,
pattern of inheritance and regulated exon splicing, all can contribute to expressivity of even monogenic traits with ~100%
penetrance. I will describe how inheritance pattern can allow some degenerative disorders of infancy express as a
neurodevelopmental disorders. Finally, our investigation of genetic disorder MICPCH challenges many of the established
molecular function of CASK, compelling us to reinvestigate this molecule. |