Table 2.

Inclusion and exclusion criteria and demographics of recruited individuals

Inclusion criteria
Individuals of any age considered likely to have a monogenic disorder
Complexity of medical care (minimum two out of three)
• Multiple organ systems involved and managed by 3 or more specialty units
• Severe condition with high morbidity and mortality
• Severe limitations on function and activities of daily living
Appropriate for trio sequencing
• Both biological parents available
• Non-specific phenotype with a broad differential diagnosis
• Possibility of blended phenotype
Exclusion criteria
Phenotypes which are typically multi-factorial or environmental-related
Unrecognised novel phenotypes with no evidence-based gene list (e.g., orphan syndromes) better suited to gene discovery projects
Prior sequencing of candidate genes (excepting genes in which variant types are poorly detected by exome sequencing, such as copy number variants, nucleotide repeat disorders, methylation testing or mitochondrially encoded variants)
Individuals who have been evaluated by specialists for diagnostic purposes for more than 2 years
Demographics
Proposed for recruitment	37
Excluded	7
Reasons for exclusion	Investigated > 2 years n = 2
	Non-genetic more likely n = 1
	Failed complexity criteria n = 3
	Microarray finding explained phenotype n = 1
Males	14 (46.7%)
Females	16 (53.3%)
Median age at recruitment (range)	21.5 months (4–650 months)
Phenotypic category	(see Supplementary Table 1 for details)
Neurodevelopmental without dysmorphism	11 (36.7%)
Neurodevelopmental with dysmorphism	9 (30%)
Multiple congenital anomalies	4 (13.3%)
Failure to thrive with neurodevelopmental issues	4 (13.3%)
Failure to thrive with dysmorphism	2 (6.7%)