Cleft Lip and Palate

• 2 distinct entities that reflect differentembryological events.

• However, they often occur together.

• Causes of both are highly heterogeneous.

Genetics of Cleft Lip And/ orPalate

• Frequency highest in Asian andAmerindians-1 in 500 or higher

• Intermediate frequencies in Caucasianpopulations

• Lowest frequency of 1:2500 in African-derived populations

Genetics of Cleft Lip And/ orPalate

• Cleft lip/palate

– 70% nonsyndromic

– 30% syndromic

• Cleft palate

– 50% nonsyndromic

– 50% syndromic

Genetics of Cleft Lip And/ orPalate

• Syndromic

– Chromosomal

– Monogenic

• AD,AR,XL

– Teratogenic e.g. phenytoin or alcohol

– Uncategorized

Complex Inheritance

• Increased risk in first degree relatives thatdrops off quickly.

• Increased recurrence risk with increasedseverity.

Genetics of Cleft Lip And/ orPalate

• Twin studies show

– Concordance in MZ twins of 40%-60%

– And DZ twin concordance of only 5%

– Lack of 100% concordance in MZ twinssuggests either incomplete penetrance orenvironmental interactions

– Higher MZ concordance strongly support amajor genetic component

Gene-Gene-Enviroment-nutrition interaction

Empiric Risk for CL/P in Relatives of AffectedProbands

30.3Third deg rel

70.7Second degrel

404.0First-degrelative

-0.1Gen pop

λ relativeIncidence ofCL/P

Populationaffected

Risk for CL/P in Sibs of Probands

8.0Bilateral CL/P

6.7Bilateral CL

4.9Unilateral CL/P

4.0Unilateral CL

Incidence in sibsPhenotype of proband

Recurrence Risks for Clefts inSibs of Proband

21.118.32

11.29.91

2.32.70

Affected sibs

Mother affected

CP%CL(P)%Affcted parent

Recurrence Risks for Clefts inSibs of Proband

23.917.62

14.49.31

5.02.30

Affected sibs

Father affected

CP%CL(P)%Affcted parent

Recurrence Risks for Clefts inSibs of Proband

54.537.62

51.631.71

45.024.00

Affected sibs

Both parentsaffected

CP%CL(P)%Affcted parent

Gene Linkage/association Studies of Clefts

++/-

+/-

-

+

+/-

++/-

4p16

4q31

6p23

MSX1

++/--2p13TGFA

-/+-1q41TGFB2

++/-+1p36SKI/MTHFR

LD/TDTLinkageLocusGene

Gene Linkage/association Studiesof Clefts

+/-+/-19q13BCL3

+/-+/-17q21RARA

++/--15q11GABRB3

+-14q24TGFB3

+-11q23PVRL1

LD/TDTLinkageLocusGene

Recurrence of CL/P and CP

• Gene dosage

• Sex of the proband

• Severity of clefting

• Number of other affected relatives

• Consanguinity

• Environmental and nutritional factors

• Modifying genes