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Author: Laurie Ann Demmer, M.D.
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Non-Mendelian Genetics (Part 2)


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition, C.V. Mosby Publishing, 2005.

  • Somatic/gonadal mosaicism, chapter 4, 68-69
  • Uniparental disomy, chapter 6, 128-129
  • Genomic imprinting, chapter 4, 77-80
  • Triplet repeat disorders, chapter 4, 80-83


The student should:

  1. Understand the difference between somatic and gonadal mosaicism.
  2. Be able to recognize a pedigree in which gonadal mosaicism may account for the unexpected recurrence of a disorder within a family.
  3. Learn the mechanisms that result in uniparental disomy.
  4. Understand the meaning of imprinting, and realize that selected genes are subject to imprinting.
  5. Understand the concept of triplet repeat diseases and the correlation between earlier manifestations of clinical symptoms ("anticipation") and molecular changes.


Mosaicism is the presence of one or more genetically distinct cell lines within an individual. Somatic mosiacism usually indicates the presence of a post-zygotic mutation, which can affect a certain percentage of the cells in one or more tissues/organs. For instance, a patient can be a mosaic for Down Syndrome with a certain percentage of cells being trisomy 21 and the remainder being normal. Alternatively, somatic mosaicism can be restricted to a certain part of the body, such as Segmental Neurofibromatosis. Certain diseases are only seen in a mosaic state (ie. McCune-Albright Syndrome which causes premature puberty, café-au-lait spots and bone disease). This is probably because they are lethal in the non-mosaic state.

Gonadal mosaicism refers to the presence of a mutation in all or part of the germ line but not in the rest of the body. This implies that a mutation occurred in a precursor sperm or egg cell. All the cells derived from that one cell will also carry the mutation, while the remainder of the cells in the body will not.

A parent with gonadal mosaicism does not have the disease, and DNA analysis of the parents’ peripheral blood is negative for the disease-causing mutation. Gonadal mosaicism is usually detected when two or more offspring present with an autosomal dominant disorder, and yet there is a negative family history. Gonadal mosaicism has been observed in humans in osteogenesis imperfecta, Duchenne muscular dystrophy, achondroplasia, and hemophilia A. It is important to consider the possibility of germ line mosaicism (rather than a new mutation) when an individual presents with an autosomal dominant disorder for the first time in a family. For purposes of genetic counseling, the risk of recurrence in subsequent offspring is much higher if a parent is a gonadal mosaic, than if the affected child carries a new mutation not present in either parent. However, because it is not feasible to test individual sperm/eggs to rule in/out gonadal mosaicism, one is generally left with discussing empiric recurrence risks and offering prenatal diagnosis in all subsequent pregnancies.

Uniparental Disomy

Uniparental disomy (UPD) is defined as the presence of two homologous chromosomes inherited in part or in total from only one parent. This means that one parent has contributed two copies of a chromosome and the other parent has contributed no copies. The incidence of UPD is estimated to be as high as 2.8 to 16.5 per 10,000 conceptions. If the parent passed on two copies of the same chromosome (as results from non-disjunction in meiosis II), the condition is called isodisomy. On the other hand, if the parent provides one copy of each homolog (as results from non-disjunction in meiosis I), this is calledheterodisomy.

At the present time, the postulated mechanisms for uniparental disomy include: a trisomic conception with postzygotic loss of a chromosome, fertilization of a nullisomic gamete by a disomic gamete, or compensatory duplication in a monosomic cell.

The first proven case of UPD in humans showed exclusive maternal inheritance of chromosome 7 in a diploid patient with cystic fibrosis, very short stature, and growth hormone deficiency. This child was found to have only maternally transmitted markers on chromosome 7. In another case, use of DNA markers proved father to son transmission of hemophilia A by showing that the boy inherited both his X and Y chromosome from his father. Twenty percent of cases of Prader-Willi syndrome are due to inheritance of both copies of chromosome 15 from the patient's mother. It is important to remember that in most cases of UPD, the karyotype appears completely normal. DNA markers are the only way to determine the parent of origin for each chromosome.

  • Clinically significant when it involves chromosomes with imprinted genes.
  • Likely to have a major role in etiology of pregnancy loss and unexplained IUGR
  • Known clinical phenotypes exist with Paternal UPD 6, 11, 14, 15 and Maternal UPD 7, 14,15,16.

Genomic Imprinting

  • Refers to the differential modification of the maternal and paternal genetic contributions to the zygote
  • Some genes are expressed preferentially from the maternal or paternal alleles
  • Results in difference in gene expression, and subsequently phenotype, depending on whether the gene has been inherited from the mother or the father
  • This can lead to differences in phenotype if a patient has uniparental disomy or a heterozygous deletion for an imprinted region of a chromosome

At least 7 chromosome regions have been shown to be imprinted in the mouse. Homologous regions in the human include parts of chromosomes 2p, 4p, 5q, 6p, 6q, 7p, 7q, 9q, 11p, 16p, 16q, 19p, 20q, 21q, 22q, and X.

In pedigrees affected by a condition that results from an imprinted gene, the disease will be transmitted either from only the father (if the paternal gene is preferentially expressed), or only the mother (if the maternal gene is preferentially expressed). In the case of maternal transmission, it may be difficult to distinguish a disease caused by an imprinted gene from a disease caused by a mitochondrial DNA defect.

Mechanism of Imprinting

  • Must occur before fertilization
  • Must be able to confer transcriptional silencing
  • Must be stably transmitted through mitosis in somatic cells
  • Must be reversible on passage through the opposite parental germline (i.e., if an allele is maternally imprinted, this must be removed in the gametes of a male offspring
  • Methylation

Prader Willi and Angelman Syndromes: Imprinting

  • Both syndromes are caused by an identical deletion on chromosome 15
  • Prader Willi: (hypotonia, mental retardation and obesity) - deletion from paternal allele
  • Angelman: (severe mental retardation, movement disorder and seizures) - deletion from maternal allele

Prader Willi Syndrome: Imprinting

  • Genes from the ‘critical’ region for Prader Willi Syndrome are only actively transcribed on the chromosome marked as having been passed on from the dad
  • If the ‘critical’ region is deleted in the paternal chromosome, (and normally turned off on the maternal chromosome), then these critical genes go unexpressed, and the syndrome will result.

Angelman Syndrome: Imprinting

  • Angelman Syndrome: ‘critical’ gene is expressed only on the chromosome passed on from mom
  • Deletions on maternal chromosome 15 result in no expression of ‘critical’ gene. (Normally that gene is turned off on the chromosome marked as having come from dad)

Triplet Repeat Disorders

Genetic anticipation refers to the increase in severity of a phenotype in successive generations. The biologic basis of this phenomenon is now known to be due to specific areas of instability in the human genome. In normal individuals, the triplet repeat sequences are stable during meiosis and mitosis and the sequence copy number is transmitted as a polymorphism from parent to child. In families affected by these disorders, the area is unstable, leading to progressive amplification of the gene sequence with each succeeding generation. This molecular finding has two important clinical correlations: 1) a direct relationship between the severity of the phenotype and repeat copy number, and 2) identification of the "premutation" in a clinically asymptomatic individual.

Fragile X Syndrome

  • Most common inherited form of mental retardation (1:1000 males)
  • Due to unstable CGG repeat at Xq27 - All full mutations derive from a premutation (56-200 repeats)
  • Expansion from pre- to full mutation only occurs through female meiosis
  • Severity of disease correlates with # of CGG repeats

Myotonic Dystrophy

  • Autosomal Dominant Disease showing anticipation
  • Clinical findings include myotonia, cataracts, cardiac arrhythmias, temporal balding, endocrinopathies
  • Unstable GCT repeat in the MT-PK gene
  • Congenital form with maternal transmission only

Huntington Disease

  • Autosomal Dominant Disorder; typically without anticipation
  • Occasional juvenile-onset: always paternal transmission
  • Clinical findings include progressive involuntary movements and cognitive loss, leading to complete debilitation. Psychiatric problems (depression) also common
  • Onset typically in the 30’s and progresses for 10-20 years until death
  • Caused by expansion of a triplet encoding glutamine in the 5’ end of the gene.
  • Normal allele: 11-34 repeats - Disease allele: 42-66 repeats
  • Pre-symptomatic testing is available, but since disease is incurable, careful education and counseling need to be provided to at-risk individuals

Common Genetic Disorders Arising From Triplet Instability

Disease (Affected) Inheritance Sequence Copy Number Copy Number (Normal)
Fragile X syndrome X-linked Semi-dominant (CGG)n <30 200-6000
Myotonic Dystrophy Autosomal Dominant (CTG)n 5-37 50-2000
Huntington chorea Autosomal Dominant (CAG)n 11-24 42-86
Spinal and Bulbar muscular atrophy (Androgen receptor) X-linked Recessive (CAG)n 11-13 40-62
Spinocerebellar Ataxia, Type I Autosomal Dominant (CAG)n 19-36 43-81
Friedreich Ataxia Autosomal Recessive (GAA)n 5-33 66-1700