Genetics

Text supplied by Salim Aftimos, Paediatric Geneticist, Starship Hospital

A cleft lip/palate is caused by the failure of developmental segments of the face to join up. The lip and palate are derived from the embryonic primary and secondary palates. The primary palate contributes to the lip, anterior tooth bearing gum region and the anterior part of the hard palate. The secondary palate contributes to the posterior hard and soft palates.

The primary palate begins to form during the 4th week of gestation and the secondary palate begins to form from the 6th to 7th week of gestation. Formation of the upper lip and palate is completed by the 12th week of gestation. The primary palate is formed by fusion of the nasal and lateral maxillary processes. The secondary palate is formed from extensions of the inner side of the left and right maxilla which develop into palatal shelves and then fuse with each other and with the nasal septum. Failure of this orderly process of fusion of the primary or secondary palate will lead to ‘clefting’ in the respective areas.

Statistically, around 1 in 700 babies are born with cleft lip/palate. While we know what happens we do not know exactly why. The general view is that it is a combination of genetic and environmental factors, which cause a child to be born with a cleft lip and/or palate.

Genetics of Cleft Lip and Palate

Cleft Lip (CL) and Cleft Palate (CP) may occur independently or together, and may be unilateral (one side only) or bilateral (both sides). In most children the cleft is an isolated malformation. In some, there may be associated malformations affecting other organs. These tend to occur more commonly with isolated cleft palates and least commonly with isolated cleft lips. In a few children there may be a recognisable pattern of anomalies which denotes a “syndrome”.

Syndrome

A syndrome may be caused by a chromosomal abnormality where there may be either additional or deleted chromosomal material. A chromosome test is requested if this is suspected. The standard chromosome test does not identify if a tiny (submicroscopic) segment is missing. If there is a clinical suspicion, additional “FISH” tests may be requested to identify such a tiny segment. An example is the FISH test for the 22q deletion syndrome.

Single Gene Disorder

In some children or families cleft lip/palate may be caused by a single gene disorder. Genes are segments of DNA that code usually for certain cellular proteins and are scattered throughout our 23 pairs of chromosomes. There may be 30,000 or more of these genes. A mutation, which is a ‘spelling mistake’ in a gene, may cause either familial forms of isolated CL/P, or syndromic forms of CL/P.

Isolated CL/P

Familial forms of isolated CL/P may follow a dominant pattern of inheritance in which case the cleft may be passed on from one generation to the next. More rarely, there may be an X-linked pattern where female gene carriers may manifest milder or absent symptoms.

There are more than 300 syndromic forms of CL/P, most of them being very rare. These may follow dominant, X-linked or recessive patterns of inheritance. In a recessive situation, the affected child is the first to manifest the disorder in the absence of a family history, but there is a risk for subsequent siblings to be affected.

Multifactorial Cause

In most children born with CL/P however, the “cause” is termed “multifactorial”. This means there may be a small change in one or more of a number of CL/P susceptibility genes, which may interact with some environmental factors, such that a threshold is reached above which a cleft may be formed. Environmental factors may include maternal factors such as diabetes, intake of certain medications such as anticonvulsant drugs, or dietary factors (vitamin levels, alcohol, smoking), etc…

Recurrence Risk

The recurrence risk for CL/P will depend on its classification, whether it is isolated, familial, syndromic, etc… In most cases where the etiology is multifactorial an empirical recurrence risk is offered. The figure is based on previous population studies of a large number of families. Such figures should be interpreted as reasonable guidelines, rather than precise measurements.