Recognition of congenital heart defects caused by CHD7 gene mutations

CHARGE syndrome occurs in at least 1 in 10,000 newborns. The most important
features are Coloboma of the eye, Heart defect, Atresia of the choanae,
Retardation of growth and/or development, Genital abnormalities, Ear
abnormalities and deafness. Up to 80% of children with CHARGE syndrome have a
congenital heart defect (CHD).
In 2004, we identified CHD7 as the causative gene for CHARGE syndrome. The
mutation detection rate varies from 65% in patients suspected of having CHARGE
syndrome to over 90% in those with typical CHARGE syndrome. The syndrome has a
very broad clinical spectrum; the occurrence of the main symptoms varies
considerably, even in patients with a proven CHD7 mutation. Since the discovery
of the CHD7 gene, it has become clear that predominantly severe mutations cause
the full clinical spectrum of CHARGE syndrome. However, an increasing number of
CHD7 mutations are being identified in patients with a milder phenotype and
some in children with a heart defect but not typical CHARGE syndrome. Thus the
clinical diagnosis of patients with CHD7 mutations can be difficult in early
infancy. There are two reasons why it is important to identify CHD7 mutations
in these children. Firstly, their paediatrician can be informed about the risk
of co-morbidity, e.g. visual, hearing, balance, kidney function, growth and
puberty development. Timely recognition of co-existing problems can improve
intervention and therapy. Secondly, information about the aetiology of the
heart defect is relevant for the recurrence risk. At this moment clinical data
of a unique group of over 300 patients in whom a CHD7 mutation has been found
are collected to delineate the occurrence and types of CHDs found in these
children (pilot study). In the current study we hypothesise that CHD7 mutations
may be present in patients with a CHD without initial suspicion of CHARGE
syndrome.

Our primary objective is to identify the patients with congenital heart defects
in whom CHD7 mutation detection is needed. Secondly we want to identify the
co-existing medical problems in children with a congenital heart defect due to
a CHD7 mutation.

We will perform analysis of the CHD7 gene and collect the clinical data of
selected patients. If a mutation in CHD7 is found, the patients will have a
once only physical examination by the researcher.

The DNA of the patients with CHDs is already available and was collected for
previous research projects or for the purpose of a diagnostic test. If the
amount of DNA appears to be insufficient, the patient/parents will be asked for
a sputum sample. So patients wil not undergo invasive procedures.
We fully realise that finding a CHD7 mutation may not only be a relief for the
patient and his/her parents and important for clinical follow-up and recurrence
risk, but it may also give rise to uncertainty and fear. Genetic counselling
and written information will be offered to all patients/parents, as well as to
their doctors, to explain the implications of the CHD7 mutation. Monitoring at
the UMCG*s multidisciplinary outpatient clinic for children with CHARGE
syndrome will be offered (see www.umcg.nl/patienten/polis/chargepoli).