Inheritance patterns and segregation data

Mendelian inheritance patterns

The current variant classification recommends interpreting the variant pathogenicity with respect to a condition and its inheritance pattern. This means the c.1521-1523delCTT (p.Phe508del) variant in the CFTR gene is considered pathogenic for the autosomal recessive condition cystic fibrosis.

The pedigree of the family with disease-causing variants should be carefully examined if it is available. What are the possible modes of inheritance of the condition in the proband? What are the variants under consideration? Do the disease mechanism and inheritance pattern support the disease causation by the variant at the given loci?

Consider all the possible scenarios and inheritance patterns for the variant and the disease in question: autosomal dominant (inherited), autosomal dominant (de novo), autosomal recessive, X-linked (inherited and de novo), mitochondrial, and mosaic state, variable expression and reduced penetrance.

Caution is advised when allelic disorders are considered. For example, variants in PTHR1 result in four disorders inherited in autosomal recessive and autosomal dominant fashions. The variant classification is specific to the mode of inheritance and disease mechanism. These conditions also demonstrate a variant effect size.

Segregation

All efforts should be made to collect the segregation data for the variant in the family members (affected and unaffected), and from distant relatives (as they are more useful). Genotyping the parents helps to determine the de novo status which can be used in the ACMG/AMP classification using the criteria PM6 (assumed de novo but without confirmation of paternity and maternity) and PS2 (de novo, both maternity and paternity confirmed, in a patient with the disease and no family history). For recessive conditions, genotyping can determine the phase of the variants, i.e. cis or trans states, which relate to ACMG/AMP criteria BP2 (observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern) and PM3 (for recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient). The lack of segregation data is often the reason for our inability to classify the variants correctly.

While a lack of segregation with the phenotype is evidence against pathogenicity (BS4, lack of segregation in affected members of a family), segregation of the variant in the family (PP1, co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease) needs careful consideration before attributing pathogenicity to it. It might reflect linkage disequilibrium and not the pathogenicity of the variant (it might be a proxy for another variant in the gene that could be in the intronic area). Segregation of the variant in multiple family members, and in multiple families from diverse ethnic backgrounds reduces the chance of linkage disequilibrium and ascertainment bias.

Variable expression of the disease, reduced or age-dependent penetrance, and biological relationships (non-paternity, assisted reproduction, etc.) are other considerations while evaluating segregation data.