Table 1.

Main modes of inheritance with recurrence risk and additional information.

Mode of inheritance	Affected allele	Origin	Risk to offspring of inheriting the variant	Risk to siblings of inheriting the variant	Additional information
Autosomal dominant	One variant allele – heterozygous pathogenic variant	Inherited De novo	50% 50%	50% < 1 % (due to parental germline mosaicism that had been detected in <10% of cases [65])	Penetrance (some individuals with the variant allele may not be affected) Phenotypic expressivity (spectrum and severity of phenotype may differ between carriers of the variant) Note: phenotypes due to de novo variants are often severe and affected individuals may not reproduce
Autosomal recessive	Two variant alleles - homozygous (same variant) or -compound heterozygous (two different variants)	One from each parent (rarely one inherited and one de novo)	Zygosity in offspring depends on carrier status of partner	25%	Heterozygous carriers of one of the variants are usually unaffected
X-linked	Hemizygous in males (one variant allele with no second allele)	Maternally inherited	All daughters are carriers, all sons are unaffected	50% of sisters are carriers, 50% of brothers are affected	Heterozygous females are usually unaffected
		De novo		< 1% for brothers (due to parental germline mosaicism that had been detected in <10% of cases [65])
	Heterozygous in females	Inherited	50%	Maternally transmitted: 50% Paternally transmitted: sisters 100%, brothers unaffected	Hemizygosity in males may be severe or even incompatible with life
		De novo	50%	< 1 % (due to parental germline mosaicism that had been detected in <10% of cases [65])
	Homozygous/compound heterozygous in females	One from each parent (rarely one inherited and one de novo)	Daughters are carriers, all sons are unaffected	Heterozygous mother: 50% affected/50% carriers Homozygous mother: 100% of offspring is affected	Rarely in epilepsies
Mitochondrial	Mitochondrial genome	Maternally inherited	Maternally transmitted: variable (depending on level of heteroplasmy) Paternally transmitted: 0%	Maternally transmitted: variable (depending on level of heteroplasmy) Paternally transmitted: 0%	Both females and males can have mitochondrial disease but only females transmit the disorder to their offspring [67]
Mosaic	Heterozygous in a fraction of cells/tissues	Post-zygotic de novo (after the 1-cell stage)	0% if germline is unaffected Up to 50% if germline is affected by mosaicism	0%	Detection depends on variant allele fraction and tissue being analyzed