Identifying health problems in people with severe and profound disabilities and genetic syndromes can be problematic, and unidentified or unmanaged health problems may adversely impact an individual's quality of life. The authors studied carer-reported contemporary health problems in three genetic syndromes (Angelman, Cornelia de Lange, and Cri du Chat syndromes) associated with severe and profound disabilities and investigated the association of these problems with affect. A control group of individuals with an intellectual disability of heterogeneous causes was used. A carer-report questionnaire was used to collect the data. Health problems were classified using Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria. Negative affect was assessed using the Mood, Interest and Pleasure Questionnaire. Half of the total sample reported at least one health problem. The nature of the health problems varied across groups, with particularly high levels of diseases of the nervous system seen in Angelman syndrome and diseases of the digestive system in Cornelia de Lange syndrome. Correlational analysis across the groups revealed a positive association between negative affect and the presence of a health problem. High levels of health problems occur in this population with certain problems associating with particular syndromes. The authors concluded that these problems seem to have a negative impact on individual affect, although further research investigating this relationship is needed.