So, monogenic disorder, let's describe that. It's primarily caused by variant of a single gene. So, it's like you have kind of like one-to-one relationship, and there's a discernible inheritance pattern, and multiple family member may have the same condition. And maybe due to a novel mutation, in that case, like parents do not carry any variant, but then child has a condition, and that's novel. When they do trio, like parents and a child, and you see there's a variant present in a child, that's probably causal for this disease that child has, but parents do not carry. That's novel mutation, which could be also more dominant type than disease manifests in those kind of cases. And disease onset is commonly at birth in childhood, or young adult. Exceptions do exist like Huntington's disease, but young adulthood. So, our patient, her first episode of pancreatitis is in her 20s, early 20s, so there's a hint that this patient may have a monogenic disorder. That's the first hint that we had. And it's a qualitative trait, which means we can describe the disorder by like certain trait or phenotype. And the phenotype is less likely to be influenced greatly by the different environment. So, even if you find a patient in U.S. versus another country, the phenotype tend to be very similar. And linkage analysis was in the past used for localization of the mutation, but now next generation sequence changed the whole molecular genetics field, and linkage analysis is rarely done. So, let's describe the inheritance patterns. Autosomal dominant inheritance is a phenotype is expressed when one variant is present on one allele of a particular gene. So, that's a common type of inheritance pattern, but there are several kinds. And pure dominant describes when homozygous compounds, heterozygous and heterozygous all have a similar phenotype and maybe indistinguishable, which is a rare case, but maybe like Huntington, maybe one example that a heterozygous even have a severe phenotype like a homozygous or compound heterozygous. But typically, it's incompletely dominant or semi-dominant disorders, which are homozygous or compound heterozygous variant have a more severe phenotype than heterozygous variant, which is like in familiar hypercholesterolemia when someone's homozygous or compound heterozygous, they have a much severe cholesterol elevation and they may have a first cardiac event in childhood versus in adulthood. So, one term that often mistaken by many individuals talking about autosomal dominant inheritance is codominant inheritance. So, this is often confused term. This describes that each allele has a specific phenotype and their strength of expression is about the same as the other one. So, they're independently different, but they're expressed similarly. So, if you see the father having A, A, A and O genotype, she has B and O genotype. So, you could have a child with A, O or A, A, B or B, O or O, O. But these phenotypes are expressed very similar and they have independent expression. So, autosomal dominant inheritance, each child has 50% chance of inheriting the variant. So, if father is affected with a autosomal dominant variant, then each child, male or female, there's no sex differentiations, could be affected 50% of the time. So, autosomal recessive is also common. This is often seen in enzyme deficiencies, autosomal recessive patterns. So, this is when both parents carry a variant. So, when a child inherits both variants from both parents, then disease can manifest. So, there's 25% of chance that the child has a disease, that the parents are carriers. And 50% of the time, they can, they're also carriers like parents. So, they have a chance to pass on a disease if they marry somebody with the same type of variant. So, there's 25% that none of the variant is inherited. So, three-fourths of the time, the child look, appears quote-unquote normal in autosomal recessive cases. So, let's talk about X-linked inheritance, which is a totally different types of inheritance pattern, because there's no male-male transmission. So, X-linked recessive, a phenotype that's first only hemizygous male and not in heterozygous females. So, females would be a carrier of the variant, but not expressing the phenotype, unless both alleles are affected. So, there's no, because a male child inherits Y chromosome from the father, no X from the father. So, there's no male-to-male transmission. So, X-linked dominant is a little bit different case, although there's no transmission from male-to-male also, but then female can manifest the disease when she inherits X chromosome from the father who has the disease. What male child can only inherit when mother has the X-linked dominant disease, but there's no male-to-male transmission in that kind of case. So, there are other rare types of inheritance patterns that I'm just briefly mentioned. X-linked, I mean, Y-linked, it's only on Y chromosomes. So, there's only Y male-to-male transmission. Female doesn't have any Y chromosomes, so there's no female affected with the condition. And mitochondria disorder, we already kind of mentioned that it's maternal transmission. So, mother can pass on mutation that's in mitochondrial genome, but father would not pass on even if he himself had condition. So, there are two terms that also get confused often. It's reduced penetrance or penetrance versus variable expressivity. So, penetrance describes all unknown phenomena. So, reduced penetrance or incomplete penetrance, meaning it's a phenotype, is not expressed in someone individual with a particular variant. So, it may appear that disease skipped a generation. So, here's the grandmother having a disease condition and then grandkids having a condition, but this father, even though he carried the variant, he's not manifesting any phenotype. Retinoplastoma is one example of this disorder, but typically is on the right variable expressivity. That means people having variant, the same variant, expresses a little bit differently. So, a degree of severity of a condition may be a little bit different in individuals. It could be then due to other gene interaction in the family, but other genes that are transmitted in the family, but this is a typical case. And even in a case, the daughter has the severe condition with pancreatitis and hypertriglycidemia, but then nobody else seems to have any other features. But we believe that at this point, it's inherited. So, one more interesting disorder that I'm just going to mention, that you have heard at least once. So, it is an imprinting disorder. It's a burnt DNA methylation occurring at typically differential methylated regions. So, there is a portion of chromosome that's only methylated by male or female. So, 15q is one of those locations that, so prediwilly, certain genes are methylated in maternal side. So, maternal genes are not expressed and only paternal genes are expressed. So, if it happens that there's some deletion of the paternal allele, abnormality can be manifested because there's no rescue from the maternal side. So, this opposite is true with Angelman syndrome. So, it's paternal imprinting, meaning paternal genes, certain genes are not expressed, but maternal genes are expressed. And especially in the neurons, there's a UBE3A, ubiquitin ligase A gene that's really important in neurons, that's only expressed from the maternal side. So, if this is missing by deletion or a burnt methylation, methylated and silenced, then Angelman syndrome can manifest. Interesting, right? Like, it's mostly in the neurons for the paternal imprinting. So, uniparental disomic disorder is another situation that this can occur, especially if it includes differentially methylated regions received from... So, this is a part of the chromosome only received from one parent and no copies from the other parents. So, it is usually received one chromosome from one parent and another chromosome from another parent. But there are aberrant situations that happens in disomic oocyte can combine with the haploid spark, then trisomic conceptus can go through trisomic rescue because three chromosomes in a cell is not stable. But it happens that one of the cells could have both of the maternal chromosomes instead of having one paternal chromosome. In that situation, the genes which should be expressed from the paternal genes are not expressed. That can manifest as predatory syndrome. So, another situation is no somatic oocyte. So, there's no chromosome in there for the particular chromosome and combines with haploid sperm. And there's only one sperm from... One chromosome from the sperm. But one chromosome is unstable. So, it goes through duplication. But unfortunately, both of the chromosomes come from the father. There's no contribution from the mother. So, if there are genes that need to be expressed from the maternal chromosome, then this is missing. And that can result in Enderman syndrome. Because paternal genes are imprinted, meaning not expressing this region of the chromosome. Other disorders of imprinting and uniparental disomy that are interesting are Beckwith-Biedemann and Russell-Salvo syndrome. But Prader-Willi and Enderman are most well-known syndromes associated with these disorders.

monogenic disorders

inheritance pattern

variants of single gene

autosomal dominant

autosomal recessive