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IMF-069-01-0001-en	Why is a gene more than its protein-coding sequence?	Promoters, enhancers, silencers, untranslated regions, splice sites and other regulatory elements determine when and where the product is made.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0002-en	How do epigenetic states differ from sequence variants in stability and responsiveness?	They can persist through cell division without changing the nucleotide sequence, yet remain responsive to development and environment.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0003-en	What distinguishes the consequence of meiotic nondisjunction from a mitotic error after fertilisation?	Nondisjunction can produce aneuploid gametes, whereas a mitotic error after fertilisation creates mosaic cell populations within one person.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0004-en	Why can the same mitochondrial variant cause different severity among relatives and affect some organs more than others?	Heteroplasmy creates tissue-specific mutant loads, and threshold effects mean organs with high energy demand are affected once the load is high enough.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0005-en	Why is a synonymous variant not always functionally silent?	Even without changing the amino acid, it can alter codon use, splicing, or messenger-RNA structure or stability.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0006-en	How can a structural variant cause disease without altering any coding base of the gene?	It can change dosage, create a fusion, or separate the gene from its regulatory elements, as well as interrupting the gene itself.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0007-en	What distinguishes haploinsufficiency from a loss-of-function disorder that requires both copies to be lost?	In haploinsufficiency one remaining functional copy cannot supply enough product, so losing a single copy causes disease.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0008-en	How does a dominant-negative variant differ mechanistically from a gain-of-function variant?	A dominant-negative protein interferes with the product of the normal allele, whereas gain of function increases or creates activity.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0009-en	Why is naming the gene involved not equivalent to explaining pathogenesis?	The same gene can cause different disorders through different molecular mechanisms, so the mechanism of the variant must be specified.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0010-en	Why should a variant of uncertain significance not direct irreversible management?	It is not a positive diagnosis, so acting on it without additional evidence risks irreversible treatment for an unproven cause.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0011-en	A child has a de novo dominant variant and both parents test negative in blood. Why can recurrence risk still exceed the population baseline?	Parental germline mosaicism can carry the variant in gametes without it being detectable in blood.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0012-en	Two carrier parents already have one affected child. What is the probability for the next pregnancy, and why?	One in four, because each pregnancy between two carriers is independent of previous outcomes.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0013-en	Why can a heterozygous individual show symptoms of an X-linked recessive disorder?	Skewed X inactivation or tissue-specific effects can leave the variant X active in enough cells to produce disease.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0014-en	Why can the same deletion or uniparental disomy produce different syndromes?	With genomic imprinting, expression depends on parent of origin, so the effect differs according to whether the affected chromosome came from the mother or father.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0015-en	What biological mechanism classically underlies anticipation, and what can mimic it?	Unstable repeat expansions cause earlier or more severe disease across generations, but ascertainment bias can create a similar impression.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0016-en	Why does a high heritability not show that an individual's trait is genetically determined?	Heritability is a population statistic for a particular environment, describing how much observed variation is attributable to genetic differences, and it changes when environments change.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0017-en	Under a multifactorial threshold model, why is recurrence risk not a simple Mendelian ratio?	Combined liability must cross a developmental threshold, so risk depends on relationship, severity, number of affected relatives, sex distribution and population frequency.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0018-en	Why may a polygenic score perform poorly in a population unlike its discovery cohort, and what is the risk?	Allele frequencies, linkage disequilibrium, environments and healthcare differ, and use without representative validation may widen inequity.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0019-en	What distinguishes locus heterogeneity from allelic heterogeneity?	Locus heterogeneity is different genes producing similar phenotypes; allelic heterogeneity is different variants in one gene causing the same or related disease.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0020-en	Why can a blood test miss a somatic mosaic variant, and what governs how widely it is distributed?	A post-zygotic variant may be confined to skin, brain, tumour or other tissue, and the earlier the developmental event, the broader its distribution may be.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0021-en	Why can a genomic disorder be present despite an apparently negative family history?	The condition may be de novo, recessive, incompletely penetrant or misdiagnosed, or hidden by small family size, early death or adoption.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0022-en	A tumour sequencing result suggests inherited predisposition. What is required before treating it as germline, and why?	Confirmation in a non-tumour sample, because tumour variants may be somatic, acquired only in the tumour rather than present throughout the person.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0023-en	Why does a pharmacogenomic genotype not replace clinical monitoring?	Genotype is only one contributor to dose and safety; effect size, ancestry, interacting drugs and organ function also determine the response.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending
IMF-069-01-0024-en	Why is a bounded uncertainty sometimes the scientifically honest conclusion of genomic reasoning?	Each link from variant to presentation needs evidence, while normal variation is extensive, databases are incomplete and interpretation changes, so a plan for further study or reinterpretation is needed.	Integrated Medical Foundations; chapter 69, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 3f95206ed188d81602abd040745ae49fc8c37501320479f5d0bef0aa122c7410; editorial review pending	imf lang::en chapter::069 module::069-01 review::pending