Inheritance status

MCNV2 classifies each offspring CNV as inherited (True) or non-inherited (False) based on parental CNV data.

This page provides a comprehensive explanation of the two inheritance modes available in MCNV2.

Overview

Inheritance status is calculated using two approaches:

CNV-level matching (coordinate-based) → Column: Transmitted_CNV
Gene-level matching (gene-based) → Column: Transmitted_gene

Both approaches are computed during the Preprocessing step and stored in the inheritance status table.

CNV-level matching (Transmitted_CNV)

Note

Definition:

A child CNV is considered inherited (True) if it has reciprocal overlap ≥ threshold with at least one parental CNV of the same type (DEL or DUP) on the same chromosome.

Algorithm:

For each child CNV:

Find all parental CNVs (father and mother) on the same chromosome with the same type (DEL or DUP)
Calculate reciprocal overlap with each parental CNV:

\[\text{Reciprocal overlap} = \frac{\text{Overlap length}}{\min(\text{Child CNV length}, \text{Parent CNV length})}\]
If reciprocal overlap ≥ threshold (e.g., 50%) with at least one parent → True (inherited)
Otherwise → False (non-inherited, candidate de novo)

Example:

Child CNV:   chr1:1,000,000-1,100,000 (100 kb deletion)
Father CNV:  chr1:1,020,000-1,120,000 (100 kb deletion)
Mother:      No overlapping CNV

Overlap length: 80 kb (1,020,000 to 1,100,000)
Min length: 100 kb
Reciprocal overlap: 80 / 100 = 0.80 (80%)

Threshold: 0.5 (50%)
Result: 80% ≥ 50% → Transmitted_CNV = True (inherited from father)

Advantages:

Simple and intuitive
Works for all CNVs (genic and intergenic)
Standard approach in CNV literature

Limitations:

Requires defining an overlap threshold (no consensus on optimal value)
Sensitive to breakpoint differences — may miss true inheritances when child and parent CNVs have slightly different boundaries
Sensitive to CNV fragmentation — a CNV detected as multiple fragments may not be recognized as inherited even if it represents the same parental CNV (e.g., child fragments: 150kb + 200kb + 50kb vs parent: single 400kb call)

Gene-level matching (Transmitted_gene)

Note

Definition:

A child CNV is considered inherited (True) if at least one affected gene is also affected by the same CNV type (DEL or DUP) in at least one parent.

Algorithm:

For each child CNV-gene pair:

Identify all genes overlapping the child CNV
For each gene, check if it is also affected by the same CNV type in the father or mother
If yes → True (inherited)
If no → False (non-inherited)
If CNV is intergenic (no gene overlap) → “intergenic”

Example 1: Same type (inherited):

Child CNV:   chr1:1,000,000-1,100,000 (DEL, overlaps genes A, B, C)
Father CNV:  chr1:1,050,000-1,150,000 (DEL, overlaps genes B, C, D)
Mother:      No CNVs affecting genes A, B, C

Gene A: Not in father (DEL) → Transmitted_gene = False
Gene B: In father (DEL) → Transmitted_gene = True
Gene C: In father (DEL) → Transmitted_gene = True

Example 2: Different type (not inherited):

Child CNV:   chr1:1,000,000-1,100,000 (DEL, overlaps gene BRCA1)
Father CNV:  chr1:1,020,000-1,150,000 (DUP, overlaps gene BRCA1)
Mother:      No CNVs

Gene BRCA1 is deleted in child but duplicated in father
→ Different CNV types
→ Transmitted_gene = False

Advantages:

Robust to breakpoint variability and CNV fragmentation
Focuses on functional impact (affected genes)
Useful for evaluating gene-based filters
No threshold parameter required

Limitations:

Only applicable to genic CNVs
Intergenic CNVs are flagged as “intergenic” (not True/False)

Comparison of the two approaches

Aspect	Transmitted_CNV	Transmitted_gene
Method	Coordinate overlap	Shared genes
Threshold	User-defined (e.g., 50%)	Not required
Applicable to	All CNVs	Genic CNVs only
Robustness to breakpoint shifts	Low (sensitive to boundaries)	High (ignores boundaries)
Robustness to CNV fragmentation	Low (fragments may fail threshold)	High (focuses on shared genes)

Tip

Recommendation:

Use both approaches to get a comprehensive view of CNV quality. The difference between CNV-level and gene-level MP highlights the impact of breakpoint variability and CNV fragmentation in your dataset.

Example use cases

Case 1: Inherited by both methods

Child:  chr1:1,000,000-1,100,000 (DEL, overlaps gene X)
Father: chr1:1,000,000-1,100,000 (DEL, overlaps gene X)

Transmitted_CNV: True (100% overlap)
Transmitted_gene: True (gene X deleted in father)

Interpretation: High-confidence inherited CNV.

Case 2: Inherited by gene, not by CNV (breakpoint shift)

Child:  chr1:1,000,000-1,100,000 (DEL, overlaps gene X)
Father: chr1:1,200,000-1,300,000 (DEL, overlaps gene X)

Transmitted_CNV: False (no coordinate overlap)
Transmitted_gene: True (gene X deleted in father)

Interpretation: Different breakpoints, but same gene affected. Likely inherited despite coordinate mismatch.

Case 3: Inherited by gene, not by CNV (fragmentation)

Child:  chr1:1,000,000-1,150,000 (DEL, 150kb, overlaps gene X)
        chr1:1,150,000-1,350,000 (DEL, 200kb, overlaps gene X)
        chr1:1,350,000-1,400,000 (DEL, 50kb, no gene)

Father: chr1:1,000,000-1,300,000 (DEL, 300kb, overlaps gene X)

Transmitted_CNV: Fragment 1 (100% overlap) → True
                 Fragment 2 (75% overlap) → True if threshold ≤75%, False if >75%
                 Fragment 3 (0% overlap) → False

Transmitted_gene: All fragments overlapping gene X → True

Interpretation: CNV fragmentation causes some fragments to fail coordinate matching, but gene-level matching correctly identifies inheritance.

Case 4: Non-inherited (candidate *de novo*)

Child:  chr1:1,000,000-1,100,000 (DEL, overlaps gene X)
Father: No CNV affecting gene X
Mother: No CNV affecting gene X

Transmitted_CNV: False
Transmitted_gene: False

Interpretation: Candidate de novo CNV or technical artefact.

Case 5: Intergenic CNV

Child:  chr1:10,000,000-10,050,000 (DEL, intergenic)
Father: chr1:10,000,000-10,050,000 (DEL, intergenic)

Transmitted_CNV: True (100% overlap)
Transmitted_gene: "intergenic"

Interpretation: Inherited based on coordinates. Gene-based method not applicable.

Case 6: Different CNV type

Child:  chr1:1,000,000-1,100,000 (DEL, overlaps gene X)
Father: chr1:1,000,000-1,100,000 (DUP, overlaps gene X)

Transmitted_CNV: False (different types)
Transmitted_gene: False (different types)

Interpretation: Same coordinates but opposite CNV types. Not inherited.