1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Campomelic dysplasia (CD; campomelic dwarfism, campomelic syndrome, camptomelic dwarfism, camptomelic dysplasia. Includes acampomelic campomelic dysplasia (ACD))

1.2 OMIM# of the disease

114290.

1.3 Name of the analysed genes or DNA/chromosome segments

SOX9.

1.4 OMIM# of the gene(s)

608160.

1.5 Mutational spectrum

The majority of mutations are point mutations (missense, nonsense, splice site mutations), but also short insertions/deletions causing frameshifts.1 Missense mutations cluster exclusively in the DNA-binding HMG domain,1 but for two that have been found so far in the dimerization domain of SOX9.2, 3 Larger deletions covering SOX94, 5 or located upstream of SOX95, 6 have occasionally been described. A few percent of cases are due to inversions or translocations interrupting the 1-Mb regulatory domain of SOX9.7, 8, 9, 10 A single publication describes cases with brachydactyly and anonychia, a phenotype compatible with Cooks syndrome MIM 10699511 due to microduplications of noncoding elements 5′ of SOX9. Missense mutations and translocations are overrepresented in CD cases without overt bending of the long bones (ACD).10, 12, 13, 14 Of note, individuals with translocation breakpoints or deletions located greater than 1 Mb upstream of SOX9 only show isolated Pierre Robin sequence and none of the other clinical symptoms of CD/ACD.15, 16 Similarly, several duplications and a deletion of a region ∼0.5 Mb upstream of SOX9 have been reported, which only lead to isolated disorders of sexual development.17, 18, 19

1.6 Analytical methods

The main strategy for mutation screening consists in sequencing of the three SOX9 exons and exon/intron boundaries, which allows for the detection of ∼90% of mutations in CD/ACD cases. This may need to be followed by screening for large deletions by quantitative PCR or array CGH, and by cytogenetic analyses to detect translocations or larger inversions, which brings the detection rate to ∼95%.

1.7 Analytical validation

The existence of a mutation is confirmed by sequencing a second, independent PCR product from the patient’s sample.

1.8 Estimated frequency of the disease

(incidence at birth (‘birth prevalence’) or population prevalence if known to be variable between ethnic groups, please report) 1 in 40 000 to 1 in 80 000.

1.9 Diagnostic setting

Comment:CD is due to de novo heterozygous mutations in SOX9, with recurrence risk of a few percent (estimate ∼5%) due to germ line mosaicism in one of the parents. A predictive prenatal testing is thus only possible if a SOX9 mutation has been identified in a previous pregnancy.

2. TEST CHARACTERISTICS

2.1 Analytical sensitivity

(proportion of positive tests if the genotype is present)About 95%.

2.2 Analytical specificity

(proportion of negative tests if the genotype is not present)100%.

2.3 Clinical sensitivity

(proportion of positive tests if the disease is present)

The clinical sensitivity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.

About 95%.

2.4 Clinical specificity

(proportion of negative tests if the disease is not present)

The clinical specificity can be dependent on variable factors such as age or family history. In such cases, a general statement should be given, even if a quantification can only be made case by case.

100%.

2.5 Positive clinical predictive value

(life time risk to develop the disease if the test is positive)

Nearly 100%. In rare instances such as far upstream translocations8, 9, 10 or upstream deletions,6 disease symptoms can be very mild so as to go unnoticed. As mentioned above, individuals with translocation breakpoints or deletions located greater than 1 Mb upstream of SOX9 only show isolated Pierre Robin sequence and none of the other clinical symptoms of CD/ACD.15, 16

2.6 Negative clinical predictive value

(probability not to develop the disease if the test is negative)

Assume an increased risk based on family history for a non-affected person. Allelic and locus heterogeneity may need to be considered.

Index case in that family had been tested:

Not applicable.

Index case in that family had not been tested:

Not applicable.

3. Clinical utility

3.1 (Differential) diagnostics: The tested person is clinically affected

(To be answered if in 1.9 ‘A’ was marked)

3.1.1 Can a diagnosis be made other than through a genetic test?

3.1.2 Describe the burden of alternative diagnostic methods to the patient

Definitive diagnosis of CD is feasible in a majority of affected individuals based on radiological findings, such as bowing of the femora and tibiae, hypoplasia of the scapulae, widely spaced vertical ischia and hypoplastic pubes, and hypoplastic cervical vertebrae. However, the molecular test for SOX9 and its regulatory domain is important for several reasons. Affected individuals with aberration of the regulatory domain and chromosome derangement tend to have better clinical outcomes. In addition, a subset of patients does not show the full skeletal manifestation, but a few skeletal changes only (eg, brachydactyly or Pierre Robin sequence).

3.1.3 How is the cost effectiveness of alternative diagnostic methods to be judged?

Not applicable. Only radiological and molecular assessments are relevant.

3.1.4 Will disease management be influenced by the result of a genetic test?

3.2 Predictive Setting: The tested person is clinically unaffected but carries an increased risk based on family history

(To be answered if in 1.9 ‘B’ was marked)

3.2.1 Will the result of a genetic test influence lifestyle and prevention?

If the test result is positive (please describe)

If the test result is negative (please describe)

3.2.2 Which options in view of lifestyle and prevention does a person at-risk have if no genetic test has been done?

(please describe)

3.3 Genetic risk assessment in family members of a diseased person

(To be answered if in 1.9 ‘C’ was marked)

3.3.1 Does the result of a genetic test resolve the genetic situation in that family?

CD is due to de novo heterozygous SOX9 mutations. Recurrence may occur due to germ line mosaicism in one parent, who may also show somatic mosaicism and may have partial manifestations. Recurrence risk for the next pregnancy cannot be determined exactly, but is estimated to be around 5%. In rare, usually milder cases, transmission of the mutation can be familial.6, 8, 9, 14

3.3.2 Can a genetic test in the index patient save genetic or other tests in family members?

Standard molecular tests of family members in addition to analysis of the index patient will not help to clarify a possible risk for parental germinal mosaicism, as only somatic mosaicism in peripheral blood DNA samples can be tested for.

3.3.3 Does a positive genetic test result in the index patient enable a predictive test in a family member?

As mentioned above, not applicable.

3.4 Prenatal diagnosis

(To be answered if in 1.9 ‘D’ was marked)

Early genetic testing from chorionic villi is possible. Routine ultrasound readily reveals bowing and shortening of the femora. However, meticulous assessment is mandatory to identify more specific findings, such as hypoplastic scapulae. CD, unlike other severe skeletal dysplasias, frequently shows only mild femoral shortening and only mild or no bowing. Thus, ‘ACD’ tends to be overlooked, although its clinical presentation is, in most cases, as severe as that of classic cases.

3.4.1 Does a positive genetic test result in the index patient enable a prenatal diagnostic?

Yes.

4. IF APPLICABLE, FURTHER CONSEQUENCES OF TESTING

Please assume that the result of a genetic test has no immediate medical consequences. Is there any evidence that a genetic test is nevertheless useful for the patient or his/her relatives? (Please describe)

A positive genetic test outcome provides an unequivocal diagnosis of CD in patients whose clinical and radiological symptoms are not clearcut. This alleviates psychological stress due to uncertain diagnosis, makes additional genetic testing for other suspected skeletal disorders obsolete and allows to offer prenatal testing in a further pregnancy at risk of recurrence of ∼5% from germline mosaicism.