Rare disorders have many faces: in silico characterization of rare disorder spectrum

Table 2 Occurrence of Human Phenotype Ontology (HPO) terms and disorder-associated genes across the rare disorder spectrum

Category	Overall	Borderline-common		Rare		Ultra-rare	D^a
Measures	Median	Median (IQR)	Adj. p-value^b	Median (IQR)	Adj. p-value^b	Median (IQR)	D^a
*Disorder-associated genes per disorder*
Associated genes	1	3 (6)	< 2.0 × 10^–16	1 (2)	< 2.0 × 10^–16	1 (0)	↓
*HPO terms per disorder*^c
Count, HPO term_total	20	17 (22)	NS	24 (24)	1.9 × 10^–06	19 (19)	–
Count, HPO term_{obligate/very frequent}	6	4 (25)	1.4 × 10^–06	6 (8)	NS	6 (8)	–
Count, HPO term_{occasional/very rare}	8	9 (15)	4.1 × 10^–02	10 (14)	2.4 × 10^–06	7 (12)	–
Ratio, HPO term _{(obligate/very frequent)/total}	0.31	0.22 (0.36)	3.7 × 10^–03	0.25 (0.33)	1.5 × 10^–04	0.33 (0.56)	↑
Ratio, HPO term _{(occasional/very rare)/total}	0.22	0.44 (0.38)	1.5 × 10^–12	0.36 (0.38)	< 2.0 × 10^–16	0.18 (0.42)	↓

A total of 2,430 rare disorders (RDs) had associated HPO terms based on Orphadata. Here, we provide counts of HPO terms for the rare disorders (RD) within the spectrum, including the ratio between them (the latter as measures of phenotypic expressivity). The measures of phenotypic expressivity are based on the HPO term occurrence within RDs. We also provide count of genes associated with the RDs. The mean ranks within the borderline-common (RD = 131) and rare (RD = 387) disorder categories were compared with those within the ultra-rare (RD = 1,912) disorder category; and the distributions are illustrated in Additional File 1: Fig. S5
^aDirection of change of proportions from borderline-common to ultra-rare (D)
^bFDR-adjusted p < 0.05 was considered statistically significant; NS refers to not significant
^cHPO term occurrence: Obligate (100%), very frequent (99–80%), occasional (29–5%), very rare (< 4–1%). The percentages indicate how many patients with a certain RD who are expected to have the HPO term in question

ISSN: 1750-1172