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Mode of inheritance rules

Information on the required mode of inheritance for variant pathogenicity in each gene is stored in PanelApp. For chromosome X, inferred sex karyotype is used to determine which rules are applied. The following variants are prioritised for each mode:

  • MONOALLELIC mode of inheritance gene variants are prioritised if detected in a heterozygous, compound heterozygous or homozygous state:
    • All prioritised variants in a green gene variant that are not homozygous for REF allele.
  • BIALLELIC mode of inheritance gene variants are prioritised if detected in a compound heterozygous or homozygous manner:
    • All prioritised variants in the gene that are homozygous for ALT allele.
    • Any prioritised variants in the green gene that are heterozygous for ALT allele if there is another prioritised variant not homozygous for REF allele.
    • for a heterozygous variant to be prioritised, the other variant in the variant group is not required to be heterozygous, i.e. compound heterozygous group can consist of one heterozygous and one homozygous variant, or two heterozygous variants.
    • two heterozygous variants prioritised in a group for under compound heterozygous segregation should be not in the same phase group.
  • X-LINKED MONOALLELIC
    • All prioritised variants in a green gene variant that are not homozygous for REF allele, both in males and females.
  • X-LINKED BIALLELIC
    • Males and XO females:
      • All prioritised variants in a green gene that are not homozygous for REF allele (we expect them to be hemizygous in a VCF file).
    • Females and individuals with minor sex karyotypes containing two or more chromosomes X:
      • All prioritised variants in the gene that are homozygous for ALT allele.
      • Any prioritised variants in the green gene that are heterozygous for ALT allele if there is another prioritised variant not homozygous for REF allele.
      • For a heterozygous variant to be prioritised, the other variant in the variant group is not required to be heterozygous, i.e. compound heterozygous group can consist of one heterozygous and one homozygous variant, or two heterozygous variants.
      • two heterozygous variants prioritised in a group for under compound heterozygous segregation should be not in the same phase group.

Segregation filter for females

The behaviour of segregation filter for X-linked biallelic mode of inheritance for females is different from the one implemented in the NHS GMS Rare Disease pipeline tiering. In the Rare Disease pipeline, single heterozygous variants are allowed to be tiered to increase sensitivity, as females sometimes can be affected due to skewed X-inactivation or have late onset, milder phenotypes. However, it is not appropriate in the newborn screening context, and only homozygous and compound heterozygous variants in females are prioritised.

Unusual sex karyotypes

Chromosome X is only evaluated in a haploid or diploid manner based or inferred sex karyotype, and variant zygosity is determined accordingly. Minor sex karyotypes with more than two chromosomes X will be analysed as diploid, and variant zygosity may be incorrectly called as a result.