Complex Multigenic Disorder

According to Vinay Kumar, et.al, complex multigenic disordersso-called multifactorial

or polygenic disordersare caused by interactions between variant forms of genes and
environmental factors. A genetic variant that has at least two alleles and occurs in at least 1% of
the population is called a polymorphism. According to the common diseasecommon variant
hypothesis, complex multigenic disorders occur when many polymorphisms, each with a modest
effect and low penetrance, are co-inherited. Example for this would be type 1 diabetes mellitus
since of the 20 to 30 genes implicated in type 1 diabetes, 6 or 7 are most important, and a few
HLA alleles contribute more than 50% of the risk. Several normal phenotypic characteristics are
governed by multigenic inheritance, such as hair color, eye color, skin color, height, and
intelligence. These characteristics (also known as quantitative trait loci[QTLs]) show a
continuous variation within, as well as across, all population groups. Environmental influences,
however, significantly modify the phenotypic expression of complex traits. For example, type 2
diabetes mellitus has many of the features of a complex multigenic disorder. It is well
recognized clinically that affected persons often first exhibit clinical manifestations of this
disease after weight gain. Thus, obesity as well as other environmental influences, unmasks the
diabetic genetic trait. Assigning a disease to this mode of inheritance must be done with caution.
Such attribution depends on many factors but first on familial clustering and the exclusion of
mendelian and chromosomal modes of transmission. A range of levels of severity of a disease
is suggestive of a complex multigenic disorder, but as pointed out earlier, variable expressivity
and reduced penetrance of single mutant genes also may account for this phenomenon.
Because of these problems, sometimes it is difficult to distinguish between mendelian and
multifactorial disorders. (Kumar, et.al, 2012)

Cytogenetic Disorder
Chromosomal abnormalities occur much more frequently than is generally appreciated.
It is estimated that approximately 1 in 200 newborn infants has some form of chromosomal
abnormality. The figure is much higher in fetuses that do not survive to term. It is estimated that
in 50% of first-trimester spontaneous abortions, the fetus has a chromosomal abnormality.
Cytogenetic disorders may result from alterations in the number or structure of chromosomes
and may affect autosomes or sex chromosomes. (Kumar, et.al, 2012)

I. Numeric Abnormalities
In humans, the normal chromosome count is 46 (i.e., 2n = 46). Any exact multiple of the
haploid number (n) is called euploid. Chromosome numbers such as 3n and 4n are
called polyploid. Polyploidy generally results in a spontaneous abortion. Any number that is not
an exact multiple of n is called aneuploid. The chief cause of aneuploidy is nondisjunction of a
homologous pair of chromosomes at the first meiotic division or a failure of sister chromatids to
separate during the second meiotic division. The latter also may occur during mitosis in somatic
cells, leading to the production of two aneuploid cells. Failure of pairing of homologous
chromosomes followed by random assortment (anaphase lag) can also lead to aneuploidy.
When nondisjunction occurs at the time of meiosis, the gametes formed have either an extra
chromosome (n + 1) or one less chromosome (n 1). Fertilization of such gametes by normal
gametes would result in two types of zygotes: trisomic, with an extra chromosome (2n + 1), or
monosomic (2n 1). Monosomy involving an autosome is incompatible with life, whereas
trisomies of certain autosomes and monosomy involving sex chromosomes are compatible with
life. Mosaicism is a term used to describe the presence of two or more populations of cells with
different complements of chromosomes in the same individual. (Aster, et.al, 2012)
II. Structural Abnormalities
Structural changes in the chromosomes usually result from chromosomal breakage
followed by loss or rearrangement of material. Such changes usually are designated using a
cytogenetic shorthand in which p (French, petit) denotes the short arm of a chromosome,
and q, the long arm. Translocation implies transfer of a part of one chromosome to another
chromosome. The process is usually reciprocal (i.e., fragments are exchanged between two
chromosomes). When the entire broken fragments are exchanged, the resulting balanced
reciprocal translocation is not harmful to the carrier, who has the normal number of
chromosomes and the full complement of genetic material. However, during gametogenesis,
abnormal (unbalanced) gametes are formed, resulting in abnormal zygotes. A special pattern of
translocation involving two acrocentric chromosomes is called centric fusion
type, or robertsonian, translocation. Difficulties arise during gametogenesis, resulting in the
formation of unbalanced gametes that could lead to abnormal offspring. Isochromosomes result
when the centromere divides horizontally rather than vertically. One of the two arms of the
chromosome is then lost, and the remaining arm is duplicated, resulting in a chromosome with
two short arms only or two long arms only. Deletion involves loss of a portion of a chromosome.
A single break may delete a terminal segment. Two interstitial breaks, with reunion of the
proximal and distal segments, may result in loss of an intermediate segment. Inversions occur
when there are two interstitial breaks in a chromosome, and the segment reunites after a
complete turnaround. A ring chromosome is a variant of a deletion. After loss of segments from
each end of the chromosome, the arms unite to form a ring. (Kumar, et.al, 2012)

III. Cytogenetic Disorders Involving Autosomes

Three autosomal trisomies (21, 18, and 13) and one deletion syndrome (cri du chat
syndrome), which results from partial deletion of the short arm of chromosome 5, were the first
chromosomal abnormalities identified. More recently, several additional trisomies and deletion
syndromes (such as that affecting 22q) have been described. Most of these disorders are quite
uncommon, but their clinical features should permit ready recognition. (Abbas, et.al, 2012)

III.a. Trisomy 21 (Down Syndrome)
Down syndrome is the most common of the chromosomal disorders. About 95% of
affected persons have trisomy 21, so their chromosome count is 47. As mentioned earlier, the
most common cause of trisomy, and therefore of Down syndrome, is meiotic nondisjunction.
The parents of such children have a normal karyotype and are normal in all respects. Maternal
age has a strong influence on the incidence of Down syndrome. It occurs in 1 in 1550 live births
in women younger than 20 years, in contrast with 1 in 25 live births in women older than 45
years. The correlation with maternal age suggests that in most cases the meiotic nondisjunction
of chromosome 21 occurs in the ovum. Indeed, in 95% of cases the extra chromosome is of
maternal origin. The reason for the increased susceptibility of the ovum to nondisjunction is not
fully understood. No effect of paternal age has been found in those cases in which the extra
chromosome is derived from the father.

In about 4% of all patients with trisomy 21, the extra chromosomal material is present not
as an extra chromosome but as a translocation of the long arm of chromosome 21 to
chromosome 22 or 14. Such cases frequently (but not always) are familial, and the translocated
chromosome is inherited from one of the parents, who typically is a carrier of a robertsonian
translocation. Approximately 1% of patients with trisomy 21 are mosaics, usually having a
mixture of 46- and 47-chromosome cells. These cases result from mitotic nondisjunction of
chromosome 21 during an early stage of embryogenesis. Clinical manifestations in such cases
are variable and milder, depending on the proportion of abnormal cells.

The diagnostic clinical features of this conditionflat facial profile, oblique palpebral
fissures, and epicanthic folds are usually readily evident, even at birth. Down syndrome is a
leading cause of severe mental retardation; approximately 80% of those afflicted have an IQ of
25 to 50. Ironically, these severely disadvantaged children may have a gentle, shy manner and
may be more easily directed than their more fortunate normal siblings. Although the karyotype
of Down syndrome has been known for decades, the molecular basis for this disease remains
elusive. Data from the human genome project indicate that chromosome 21 carries about 500
annotated genes, including approximately 170 that are conserved protein-coding genes and 5
miRNAs. It is unclear whether the phenotype of Down syndrome arises as a consequence of
increased gene dosage of protein coding genes on chromosome 21 itself or of the effects of
deregulated miRNA expression on target genes located on other chromosomes (as described
previously, miRNAs act through inhibition of target gene expression). Two chromosome 21
candidate genes, DYRK1A, which codes for a serine-threonine kinase, and RCAN1 (regulator
of calcineurin 1), which codes for a protein that inhibits a critical cellular phosphatase enzyme
called calcineurin, have emerged as the top culprits in the pathogenesis of Down syndrome.
(Abbas et.al, 2012)

III.b. 22q11.2 Deletion Syndrome
The 22q11.2 deletion syndrome encompasses a spectrum of disorders that result from a
small interstitial deletion of band 11 on the long arm of chromosome 22. The clinical features of
this deletion syndrome include congenital heart disease affecting the outflow tracts,
abnormalities of the palate, facial dysmorphism, developmental delay, thymic hypoplasia with
impaired T cell immunity, and parathyroid hypoplasia resulting in hypocalcemia. When T cell
immunodeficiency and hypocalcemia are the dominant features, the patients are said to
have DiGeorge syndrome, whereas patients with the so-called velocardiofacial syndrome have
mild immunodeficiency but pronounced dysmorphology and cardiac defects. In addition to these
malformations, patients with 22q11.2 deletion are at particularly high risk for psychoses such as
schizophrenia and bipolar disorder. The molecular basis for this syndrome is not fully
understood. The affected region of chromosome 11 encodes many genes. Among these, a
transcription factor gene called TBX1 is suspected to be responsible, since its loss seems to
correlate with the occurrence of DiGeorge syndrome. (Abbas, et.al, 2012)