multifactorial inheritance

most common cause of major anomalies observed in newborn infant

multifactorial inheritance

these are examples of...

cleft lip and palate; pyloric stenosis; clubfoot; congenital dislocation of hip, neural tube defect; peridontal disease

multifactorial inheritance

what is multifactorial inheritance

a condition where a trait or disease is caused by a combination of multiple genetic and environmental factors, rather than a single gene

(how many factors and what kind you have can dec ur threshold for a disorder)

characteristics of multifactorial causation

familial (not distinctive)

inc risk the closer you are to relative

inc risk with more affected relatives

inc risk with more severe malformations/presentations

with multifactorial causation, if there is a sex difference and the less affected sex is affected, what is the effect on recurrence risk

increases.

the less-affected sex must have a greater "liability load"—a higher level of genetic and environmental risk factors—to develop the condition, indicating that the entire family has a higher concentration of risk factors

fourth most common congenital disorder in humans

cleft lip and palate

(less common than heart defects, genital or urinary tract) (more common than spina bifida)

incidence: about 1/700 – 1/1,000 births; 15 per day in the United States

cleft lip and palate 

failure of union of frontonasal processes of face with lateral maxillary prominences at 3-4 weeks

cleft lip and palate

what union fails to form in cleft lip ± cleft palate 

union of frontonasal process of face with lateral maxillary prominences at 3-4 weeks

how are midline facial clefts different from cleft lip and palate

facial clefts result from deficient frontonasal development normally induced by underlying brain

*associated with holoprosencephaly

these clefts are commonly associated with holoprosencephaly

midline facial clefts

characteristic of a classic cleft palate

V shaped cleft

common types of cleft lip and palate

unilateral 80%

bilateral 20%

CL extending to palate 70% in unilateral cases and 85% in bilateral cases

isolated CP separate from CL and CP

do the palate and lip form at different stages

yes

what is the submucous cleft palate

hard palatine shelves dont merge + soft tissue does not form that causes asymmetric movement of pharyngeal wall

can be isolated or occur as part of a syndrome such as deletion 22q syndrome

submucous cleft palate

common finding with submucous cleft palate

bifid or double uvula is frequent finding

what syndrome can submucous cleft palate be apart of

deletion 22q11.2 di george

(may also be isolated)

U shaped cleft palate

pierre robin malformation sequence

small recessed chin which causes obstruction by tongue

cleft is due to obstruction by the tongue

U shaped cleft palate (pierre robin malformation sequence)

CP oten seen in Pierre Robin malformation sequence

U shaped cleft palate

___% of those with cleft lip/palate also have a related syndrome

30

*more are associated with cleft lip and palate but can just be associated with isolated cleft lip

most common chromosome anomalies associated with cleft lip and palate

13 and 18

Up to __% of those with cleft lip and/or cleft palate also have a related syndrome

• 7-13% with “isolated” CL are born with associated anomalies

• 11-14% with CL+CP are born with associated anomalies

• Over 300 syndromes associated with CL/CP

• Many chromosome anomalies associated, the most common are trisomies _____

30%

13 & 18

approx. 40-50% of those with only ___________ have a syndrome

*more common with this

cleft palate only

*different process

mode of inheritance of van der woude syndrome

autosomal dominant

characterized by a cleft lip and/or palate and distinctive lower lip pits

Van der Woude Syndrome

what is van der woude syndrome

congenital lip pits

can have cleft lip or palate

caused by mutations in IRF6

van der woude syndrome

CT disorder with myopia, cataracts, retinal detachment

stickler syndrome

autosomal dominant + COL2A1 mutation

stickler syndrome

characteristics of stickler syndrome

cleft palate with small jaw causing critical airway disease

mutation in ______ causes stickler syndrome

COL2A1

22q, van der woude, and stickler all have a ___% recurrence risk if inherited 

50

22q11.2 deletion syndrome (digeorge) is characterized by

a wide range of symptoms affecting multiple body systems, including congenital heart disease, impaired immunity due to an under-developed thymus, cleft palate, developmental delays, velopharyngeal Incompetence

the condition has a highly variable presentation

22q11.2 deletion can sometimes be visible by 

chromosome analysis 

how are non-syndromic CL/P a complex multifactorial trait

several genes are involved

level of penetrance varies

males and females different

environmental overlays

smaller deletions of 22q11.2 may be detected by 

smaller deletions detected by FISH or microarray

empiric data for risk recurrence of non-syndromic CL/P is dependent on what 3 things

number of other affected family members and their relationship

type of cleft

severity of cleft

some environmental causes of cleft lip and palate

amniotic band sequence

teratogens (alc, anticonvulsants, methotrexate, maternal tobacco)

you are more likley to have a child with nonsyndromic CL/P if..

there is more family history

does having a child with a more severe CL/P inc the chances of having another child with it

yes

this cleft lip and palate anomaly has a greater risk to sibs

bilateral cleft lip and palate

CL+/-P is more common in males or females

males

cleft palate is more common in males or females

females

multifactorial disorder with hardening of the pyloric sphincter

pyloric stenosis

who is more affected with pyloric stenosis

males b/c genetic threshold is lower and females require more genetic factors to be affected

who has highest risk for pyloric stenosis

male relative of an affected female

when does the neural tube form

24-28 days (before pregnancy confirmation)

3 types of neural tube defects

spina bifida- 65

anencephaly- 25

encephalocele- 10

backbone and spinal canal do not form properly in the developing fetus

spina bifida

Meninges and spinal cord tissue incorporated into the overlying skin • Open or closed

Myelomeningocele

Myelomeningocele (spina bifida)

meninges and SPINAL CORD tissue incorporated into overlying skin

-can be open or closed

Surgery within 24 hrs in this spina bfida

myelominingocele

what determines the clinical features of spina bifida

degree related to LOCATION of defect

higher of the opening, the greater the impairment

Individuals can have many disabilities:

• Partial or complete paralysis of lower extremities

• Difficulty with control of bowel and bladder function

• Anal wink

• Hydrocephalus (excessive fluid on the brain)

• Normal intelligence in ~70%, some with intellectual disability

Spina Bifida

part of skull improperly formed, part of the brain is outside (often part of a syndrome)

encephalocele

effect of encephalocele is dependent on...

size (may have physical or mental handicaps) 30% mortality

brain and skull not formed properly

anencephaly (50% miscarried or still born; if they live they die shortly after)

Tx of spina bifida

In-utero fetal surgery to minimize damage as soon as possible; long term neurological benefits

No significant difference in PROM, preterm delivery, perinatal death, maternal complications

but promising long term neurological benefits (ore likely to retain neurologic function)

spina bfida surgery

occurrence rate of ntds/spina bfida

95% with no history of neural tube defects

why are NTD a multifactorial cause

interactions between several genes and between genetic and environmental causes

may be several genes or gene combinations involved

seizure medications

• valproic acid (Depakene)

• carbamazepine (Tegretol)

are risk factors for 

NTD

risk factors of NTD

seizure medications

insulin-dependent diabetes

maternal obesity, prolonged increased maternal temperature, race

Insulin-dependent diabetes

• Maternal obesity

• Prolonged increased maternal temperature •

_{?History of celiac and other malabsorption disorders}

_{• ?History of gastric bypass}

• Race/ethnicity: hispanic women, particularly of Mexican origin, have highest risk

risk factors for ?

NTD

antieplieptic drugs and NTD

valproate

6-7% risk for malformations

spectrum of defects is broad, could be related to dose

hyperthermia and NTD

inc risk of NTD

heart defects

*should not take hot baths when pregnant; treat fevers aggressively with tylenol

atrial septal defects, hypoplastic left heart may be results of NTDs due to

hyperthermia

which genes are linked to NTD

genes for folate and glucose metabolism

what is MTHFR

enzyme used to metabolize folate

gene variants of MTHFR

C677T and A1298C

*minimal effect on risk

what percent of population has two copies of C677T

10-20%

*so dont order this test to be done b/c effect is minimal and not a lot of ppl in the pop has it

people with two MTHFR variants were thought to be at risk of... 

stroke, thrombosis, CAD, preeclamsia and placental abruption

*related to elevated homocysteine level

Having 2 mutations in ____ AND elevated_______ increases the risk of NTD’s

• About 20% of women who have a child with an NTD have abnormal ______ metabolism

• Having an adequate amount of folate reduces _______ back to normal levels

MTHFR

homocysteine

homocysteine

homocysteine

having 2 mutations in MTHFR and elevated homocysteine ...

inc risk of NTD's

effect of adequate amount of folate on homocysteine levels

returns it back to normal

why is folic acid important for spina bifida

daily intake (400ug) can reduce spina bifida up to 70%

prevents other birth defects, heart disease, CL/P, stroke, colon and cervical cancers. UTI defects

when should you take folic acid when conceiving

a month before

continuing through first few weeks of pregnancy

*FDA recommended you take it during childbearing years

foods high in folate

- LIVER

- green leafy vegetables

- grains

- legumes chickpeas

- oranges

- white bread

4 mg (milligrams) or 4000 mcg (micrograms) folic acid recommended ____________ to reduce risk of recurrence when there is a significant family history

PRECONCEPTIONALLY

folic acid reduces the recurrence of NTD's by ___%

75

*shouldnt overdose it

recurrence risk of NTD is higher if

you already have an affected child/children

multiple additive factors needed to reach disease threshold

multifactorial

locus heterogeneity

mutations in different genes can produce the same phenotype

Examples of _______

• Osteogenesis imperfecta – can be caused by a mutation in COL1A1, COL1A2, IFITM5, SERPINF1, CRTAP, LEPRE1, PPIB, or FKBP10

• Noonan syndrome – can be caused by a mutation in PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, or MAP2K1 

locus heterogeneity

does medical management change the outcomes of a multifactorial inheritance pattern or locus heterogeneity

locus heterogeneity

twins that originate from the same embryo. one zygote, a single fertilized egg (identical twins, same genetics)

monozygotic twins

twins that are great for studying the environmental effect on disease

monozygotic twins

two babies in one pregnancy who develop from two zygotes (fraternal, different genetics) double ovulation. born at the same time

dizygotic twins

what is high concordance in twins

when one twin has a trait the other will likely too (fingerprints, height, BMI, autism)

heritability equation in twins

2 x (MZ concordance - DZ concordance)

*if value is 1= highly genetic component!

1.0

what accounts for differences in monozygotic twins

diff uterine environment, postnatal environments, somatic mutations, diff methylation patterns

nucleic acid sequences

is methylation prezygotic or postzygotic change

postzygotic change (changes through life-- only twins nucleic acid sequences are identical)

psychiatric diseases are more prevalent in DZ or MZ twins

MZ

*hard to study, genetically heterogeneous, multiple suceptibility loci

multiple susceptibility loci found linked to brain-expressed proteins with glutamate receptor interactions in these disorders

psychiatric disorders

adoption studies show us that traits between child and biological parents are

less attributed to environment but more emphasis on shared genetics

why are multifactorial conditions harder to study than congenital defects

more variables and factors to look at