The portal for rare diseases and orphan drugs

About 76 patients are reported in the scientific and medical literature; however, more than 300 are known to patient organizations.

Most patients present with neonatal hypotonia and feeding difficulties, often requiring nasogastric intubation. The developmental delay and intellectual disability are of variable severity. All patients reported presented with language delay/deficits (mostly expressive limitations) and some patients are non-verbal into adulthood. About half of the patients are diagnosed with a cardiac abnormality (atrial septal defects, ventricular septal defect, patent foramen ovale and/or persistent ductus arteriosus). Other frequent problems are gastroesophageal reflux, constipation and eye abnormalities (strabismus, amblyopia and less frequently refractory errors). A facial gestalt might be recognized with a broad nasal tip, thin tented upper lip and bi-temporal narrowing. Microcephaly occurs in a minority of the patients. Other less common features are autism spectrum disorders, sleep disturbances, craniosynostosis, seizures, increased susceptibility to infections, haematological and immunological abnormalities and bowel obstruction.

The disorder is caused by heterozygous pathogenic variants affecting the KAT6A gene (8p11.21) which encodes for a lysine (K) acetyltransferase 6A that forms part of a histone acetyltransferase complex regulating transcriptional activity and gene expression. Genotype-phenotype correlations suggest that variants affecting the last two exons of the gene (16 and 17) are associated with a more severe phenotype.

The diagnosis is established by whole exome or genome sequencing or multi-gene panel including the KAT6A gene. Cases due to copy number variants might be identified by array-comparative genomic hybridization.

The syndrome has an extensive differential diagnosis in the context of syndromic DD/ID.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

The disorder is autosomal dominant. Most cases are sporadic due to de novo variants, but familial and germinal mosaicism cases have been reported. For the affected individual, the risk of transmission is 50% for each pregnancy.

Management is symptom-based and requires a multidisciplinary approach. Early speech and language therapy can improve oro-motor dyspraxia and articulation deficits. Augmentative and alternative communication tools are important aids. All patients require early cardiac evaluation with electrocardiogram and echocardiogram. Tube feeding might be required in infants, and all patients should be monitored for signs and symptoms of gastroesophageal reflux. Older patients might need long term medication with laxatives. Bowel obstruction should be considered in case of abdominal pain, and increased vomiting/reflux. Follow-up should include evaluation of behavioural/social difficulties, complete blood count and immune profile for recurrent infections, and regular assessment of vision. For sleep disorder, study of obstructive apnoea is recommended and melatonin supplementation might be considered.

Long term prognosis of the disorder is unknown.