Clinical details of patients studied

2.3.1 Nonsyndromic cleft lip with or without cleft palate

Suitable affected sib-pair families with nonsyndromic cleft lip with or without cleft palate were identified throughout the UK. Appropriate ethical approval was obtained from Great Ormond Street NHS Trust Research Ethics Committee (number 94CG01). Patients were identified through the Cleft Lip and Palate clinic at Great Ormond Street Hospital (GOSH), through the Cleft Lip and Palate Association or following a press release by Action Research. All participating families were

clinically assessed to accurately document the phenotype and exclude any underlying syndrome. This was performed by either Dr. Susan Holder or Dr. Melissa Lees. 92 complete affected sib pair pedigrees, with DNA samples from both sibs and both parents, were made available to study with an approximate male to female ratio of

3:2.

2.3.2 Hemifacial microsomia families

Numbers prefixed by a G next to the family identifier refer to files held in the Clinical and Molecular Genetics Unit at the Institute o f Child Health, London.

2.3.2.1 Family P (G14374)

The phenotype of affected individuals in this family is highly variable (see

pedigree fig. 2.1). Individuals Illn and I V 4 are the most severely affected. Individual

have macrostomia, bilateral preauricular skin tags, narrow external auditory meati, micrognathia and marked facial asymmetry. She is of normal intelligence and over the years has required repeated surgery for correction of macrostomia and micrognathia.

Her father, I I 9 , has only mild facial asymmetry and preauricular skin tags.

The first cousin once removed of III1 3 , I V 4 , is also severely affected. She was

bom with a cleft palate, macrostomia, right sided microtia with external auditory canal atresia, bilateral preauricular skin tags and micrognathia. She has also had surgery for micrognathia and macrostomia as well as cleft palate repair.

Developmental milestones have been normal although she had some speech delay, possibly secondary to her right-sided conductive hearing loss. Her heart, kidneys and

neck are normal. Her father ( I I I 4 ) has only mild facial asymmetry with scarring

following removal of preauricular skin tags, narrow external auditory meati and a slightly small jaw. He is reported also to have a horseshoe kidney.

Individual III12 is of note, she was bom with a tracheo-oesophageal fistula and

oesophageal atresia, as well as marked facial asymmetry.

DNA samples were available from 11 affected individuals from this family in addition

to individual II5, an obligate carrier of the condition (see figure 2.1).

2.3.2.2 Family R

Family R is a North American family ascertained by Dr. Robert Gorlin, University of Minnesota, USA. Limited clinical information is available on this

family. Individuals I V 1 3 , V 7 , Vg and V 9 all exhibit preauricular skin tags. Individual

IV4 is more severely affected. He has left-sided mandibular hypoplasia associated

with underdevelopment of the masseter, preauricular skin tags and an unstable temporo-mandibular joint. A small right-sided preauricular fistula was also noted. The pedigree of this family is shown in figure 2.2.

2.3.2.3 Family D1

Family D1 is a Dutch/German family ascertained by Dr. Bert de Vries, Erasmus University, Rotterdam. Figure 2.3 shows the pedigree for this family. The

proband is individual III2, who presents with facial asymmetry, microtia and vertebral

anomalies. Her son, IVi was bom with a tracheo-oesophageal fistula, hypospadias

and a horseshoe kidney. No facial asymmetry was reported. Individual III2 in this

family also exhibits microtia and facial asymmetry. All three affected individuals are described to have asymmetric thumbs.

2.3.2.4 Family H (G13559)

Individual II I 2 in this family was bom with left-sided microtia with absence of

the extemal auditory meatus and preauricular skin tags. Her sister. III], has cup shaped ears, a left-sided preauricular skin tag and bilateral preauricular pits. Their

father, individual II 2 , exhibits no features of the condition, however his sister ( I I 3 )

and her daughter ( I I I 3 ) both have left-sided preauricular skin tags. The pedigree of

2.3.2.S Family G-P (G16327)

The pedigree o f family G-P is shown in figure 2.3. The proband, individual

III2, was bom with left-sided facial asymmetry with ipsilateral facial weakness,

microtia and extemal auditory canal atresia. A sinus on the left cheek and a small

preauricular tag on the right side were also noted. His uncle, individual II3, has

preauricular skin tags and an abnormal pinna on the right side. He was also reported to have a horseshoe kidney. Individual Ii in this family has preauricular skin tags.

2.3.2.6 Sporadic eases

In addition to the familial cases, 120 sporadic cases with HFM and isolated microtia have been ascertained through the Joint Microtia Clinic at Great Ormond Street Hospital. The clinic is mn by an ENT surgeon, a plastic surgeon and a clinical geneticist. Information on pregnancy and birth history, as well as family history and DNA samples have been collected on all these cases. Ethical approval for this study was granted by the ICH/GOSH Research Ethics Committee.

The phenotype of these cases ranges from individuals with mild unilateral microtia to more severely affected cases with marked facial asymmetry, unilateral microtia with preauricular skin tags and conductive hearing loss. The male to female ratio of this

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