Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder

Table 1 Number of probands and unaffected siblings with autosomal biallelically or X-linked inherited variants

Group	Biallelic PTV (MAF ≤ 1%)	Biallelic Dmis (MAF ≤ 1%)	Biallelic Syn (MAF ≤ 1%)	X-linked PTV (MAF ≤ 0.1%)	X-linked Dmis (MAF ≤ 0.1%)	X-linked Syn (MAF ≤ 0.1%)
All genes
Shared	8	7	2	7	24	93
ASD-specific	25	32	65	55	125	392
Sibling-specific	19	30	61	15	55	202
P-value	0.45	0.89	0.79	0.015	0.22	0.55
OR	1.32	1.07	1.07	2.01	1.24	1.06
95% Cl	0.70–2.55	0.63–1.83	0.74–1.55	1.11–3.86	0.89–1.76	0.87–1.30
Brain-expressed biallelically or hemizygous constrained genes
Shared	2	3	0	1	15	63
ASD-specific	10	19	43	23	73	285
Sibling-specific	2	15	35	4	29	133
P value	0.038	0.61	0.42	0.026	0.17	0.14
OR	5.02	1.27	1.23	3.13	1.37	1.14
95% Cl	1.07–47.19	0.61–2.69	0.76–1.99	1.06–12.49	0.87–2.21	0.95–1.50

The rare recessive inherited coding variants are divided into biallelic variants (homozygous or compound heterozygous variants) in autosomes and X-linked hemizygous variants in males. “Shared” refers to the number of probands and siblings in each family who sharing a certain class of recessive inherited variants, and these were excluded from the burden analysis. X-linked inherited variants that were shared between a male proband and his male sibling were counted in the line of “Shared” and were excluded from the burden analysis. Biallelic variants were counted in 1799 probands and 1799 unaffected siblings. Inherited X-linked hemizygous variants were counted in 1571 male probands and 847 male siblings. Genes harboring a PTV and a Dmis variant in trans were included in the group of biallelic PTVs. Fisher's exact test was used to calculate p values between ASD probands and unaffected siblings. CI, confidence interval; Dmis, deleterious missense variants; OR, odds ratio; PTVs, protein-truncating variants, including stop-gain, stop-loss, splicing site variants, and frameshift indels; Syn, synonymous variants. P value below 0.05 was highlighted in bold

ISSN: 2040-2392