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In Depth Tutorials and Information
CHAPTER
9
Patterns of Inheritance in Osteogenesis
Imperfecta
Julie S. Cohen
Kennedy Krieger Institute, Baltimore, MD, USA
INTRODUCTION TO INHERITANCE
PATTERNS
A
UTOSOMAL DOMINANT O
I
The majority of individuals with OI, greater than
90%, have an autosomal dominant form due to hetero-
zygous mutations in one of the two genes encoding
type I collagen,
COL1A1
and
COL1A2
(see Chapter 10).
These mutations may be inherited from an affected par-
ent or arise de novo. The proportion of cases due to
de novo
mutations varies by severity. Approximately
60% of people with OI type I (classic non-deforming OI
with blue sclerae) or OI type IV (common variable OI
with normal sclerae) have
de novo
mutations, whereas
nearly 100% of cases of OI type II (perinatal lethal) and
OI type III (progressively deforming) are
de novo
.
An important consideration in cases of apparently
de novo
mutations (i.e., when the parents of an affected
individual do not have features of OI) is the possibil-
ity of
mosaicism
. Genetic mosaicism is defined as the
presence, in an individual or tissue, of two or more cell
lines that differ genetically but are derived from a sin-
gle zygote.
1
In other words, the mutation is present in
a portion of a person's cells, but not all cells. Mosaicism
results from a spontaneous post-zygotic mutation. The
extent of mosaicism depends on when the mutation
occurred during the process of development and cell
differentiation. The mutation may be present in a sub-
set of tissues throughout the body, which is referred to
as somatic mosaicism. Individuals with somatic mosa-
icism may have mild features of OI, or they may be
clinically unaffected. If the mutation is present in the
germ cells (i.e., eggs or sperm), then it is transmissible
to subsequent generations. When the mutation is pres-
ent only in the germ cells but not elsewhere in the body,
this is referred to as germline or gonadal mosaicism
Autosomal
disorders such as osteogenesis imperfecta
(OI) are due to mutations in genes on the
autosomes
, or
numbered chromosomes. Individuals have two copies
(alleles) of every autosomal gene, one inherited from
each parent.
Autosomal
dominant
disorders are those that result
from a mutation in one copy of the gene. Dominant
mutations may be inherited from an affected parent or
arise
de novo
. For a person affected with an autosomal
dominant disorder, there is a one in two or 50% chance
in each pregnancy of passing on the mutated gene copy
and therefore having an affected child. Likewise, there
is a 50% chance of having an unaffected child.
In autosomal
recessive
disorders, the disease only
occurs when an individual has a mutation in both gene
copies (biallelic mutations). A person may have two cop-
ies of the same mutation (homozygote) or two different
mutations (compound heterozygote). Individuals who
possess a single autosomal recessive gene mutation are
unaffected carriers of the disorder; in other words, one
normal gene copy (and therefore half the usual amount
of gene product) is sufficient for normal development
and functioning of the individual. Typically, parents of
a person with an autosomal recessive disorder are obli-
gate carriers. There is a one in four or 25% chance in each
pregnancy conceived by a carrier couple that the child
will inherit the mutated gene copy from each parent
and therefore will be affected with the disease. Likewise,
there is a three in four or 75% chance that the child
would be unaffected, either a carrier (two in four or 50%
chance) or non-carrier (one in four or 25% chance).
