ISCN-like Simple Nomenclature

Introduction

The International System for Human Cytogenetic Nomenclature (ISCN) is a standardized system used to describe chromosomal abnormalities. It is a standardized system developed to describe the banding pattern of human chromosomes as well as any structural variations. ISCN is used by geneticists and researchers to ensure clarity and uniformity when reporting chromosomal abnormalities.

The tool provides ISCN-like simple nomenclature to describe karyotype of the input in sample's and variant's level in both VCF and JSON outputs.

For VCF output, you can find them in following fields:

##INFO=<ID=NOM,Number=.,Type=String,Description="Simple ISCN-like nomanclature for each of the variants">
##FORMAT=<ID=SNOM,Number=1,Type=String,Description="Simple nomenclature of the sample"> 

For JSON output, you can find them in following fields:

{
    "header": {...},
    "positions":
    [
        {
            ...
            "samples":
            [
                {
                    ...
                    "simpleNomenclature": "Xq26.2q26.3(133042525_136149357)x2-3" // Simple nomenclature of the sample for this position
                }
            ],
            "variants":
            [
                {
                    ...
                    "simpleNomenclature": "dup(X)(q26.2q26.3)" // Simple ISCN-like nomanclature for each of the variants
                }
            ]
        }
    ],
    "genes": [...],
    "samples":
    [
        {
            "id": "FEMALE_SAMPLE",
            "simpleNomenclature": "3p21.31p21.1(47880200_53573886)x2 hmz,6p11.2(57801514_57827028)x3 hmz,Xq26.2q26.3(133042525_136149357)x2-3" // concated sample's nomenclature
        }
    ]
}

Variant's level ISCN-like Simple Nomenclature:

Key Components

• Chromosome Number: Identifies the chromosome.
• Arm: Chromosome arms are labeled "p" (short arm) and "q" (long arm).
• Banding Pattern: Each arm is divided into regions, bands, and sub-bands that are numbered starting from the centromere (central part of the chromosome).

Supported Structural Variant Types

The algorithm supports the following structural variant types:

• Deletion (del)
• Duplication (dup)
• Copy Number Gain (dup)
• Copy Number Loss (del)

Processing Details

The provided ISCN notation algorithm processes chromosomal variants and generates ISCN notation by following these steps:

1. Identify Variant Type: The algorithm recognizes several types of chromosomal variants such as duplications, deletions, copy number gains, and copy number losses.

2. Locate Cytogenetic Bands: Using the start and end positions of the variant, the algorithm identifies the corresponding cytogenetic bands on the chromosome.

3. Generate Notation: Constructs the ISCN notation string using the variant type, chromosome number, and identified cytogenetic bands.

Example

For a deletion on chromosome 8 from position 19200001 to 135400001, the algorithm would:

1. Recognize the variant type as a deletion.
2. Identify the start band as p21.3 and the end band as q24.23.
3. Generate the ISCN notation: del(8)(p21.3q24.23).

More examples:

Chromosome	Start Position	End Position	Variant Type	ISCN Notation
8	1	19200001	deletion	del(8)(p21.3)
8	1	19200001	duplication	dup(8)(p21.3)
8	19200001	135400001	deletion	del(8)(p21.3q24.23)
8	19200001	135400001	duplication	dup(8)(p21.3q24.23)
8	127300001	131500000	duplication	dup(8)(q24.21q24.22)
8	127300001	131500000	copy number gain	dup(8)(q24.21q24.22)
8	128746677	128749160	duplication	dup(8)(q24.21q24.21)
8	128746677	128749160	copy number gain	dup(8)(q24.21q24.21)
8	135400001	138900001	duplication	dup(8)(q24.23q24.3)
8	135400001	146364022	deletion	del(8)(q24.23)
8	135400001	145138635	duplication	dup(8)(q24.23q24.3)
8	135400001	138900001	copy number loss	del(8)(q24.23q24.3)
8	135400001	146364022	duplication	dup(8)(q24.23)
X	86200001	103700000	copy number loss	del(X)(q21.31q22.2)
X	86200001	103700000	deletion	del(X)(q21.31q22.2)

Sample's level ISCN-like Simple Nomenclature

Supported VCF Types

The tool supports following VCF files for sample level ISCN-like Simple Nomenclature:

• CNV
• Ploidy

CNV VCF

For CNV VCFs, the key components of the simple nomenclatures for each sample are:

1. Chromosome
2. Genetic Band of the CNV
3. Start/End Position
4. Sample's Copy Number: In the case of Mosaic Copy Number Gain Variant, we calculate the possible copy number range from the ploidy and segment mean field.
5. (Optional) Loss of Heterozygosity

An example input VCF line:

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO	FORMAT	FEMALE_SAMPLE
3	47880199	DRAGEN:CNLOH:3:47880200:53573886	N	<LOH>	100	PASS	END=53573886;REFLEN=5693687	GT:SM:CN:BC:PE	1/1:1.0:2:5694:15,15
6	57801513	DRAGEN:GAINLOH:6:57801514-57827028	N	<LOH>	100	PASS	END=57827028;REFLEN=25515	GT:SM:CN:BC:PE	1/1:1.5:3:532812:15,15
X	133042524	DRAGEN:GAIN:X:133042525:136149357	N	<DUP>	100	PASS	END=136149357;REFLEN=3106833;HET	GT:SM:CN:CNF:BC:PE	0/1:1.25:3:2.5:3106:15,15

The annotated VCF would look like:

#CHROM	POS	ID	...	INFO	FORMAT	FEMALE_SAMPLE
3	47880199	DRAGEN:CNLOH:3:47880200:53573886	...	END=53573886;REFLEN=5693687;CSQ=...	GT:SM:CN:BC:PE:SNOM	1/1:1.0:2:5694:15,15:3p21.31p21.1(47880200_53573886)x2 hmz
6	57801513	DRAGEN:GAINLOH:6:57801514-57827028	...	END=57827028;REFLEN=25515;CTB=6p11.2	GT:SM:CN:BC:PE:SNOM	1/1:1.5:3:532812:15,15:6p11.2(57801514_57827028)x3 hmz
X	133042524	DRAGEN:GAIN:X:133042525:136149357	...	END=136149357;REFLEN=3106833;HET;CSQ=...	GT:SM:CN:CNF:BC:PE:SNOM	0/1:1.25:3:2.5:3106:15,15:Xq26.2q26.3(133042525_136149357)x2-3

Ploidy VCF

For a Ploidy VCF, the key components of the simple nomenclature are:

1. Reference Sex Karyotype, which is given in the input VCF header
2. Chromosome
3. Chromosome's Ploidy Number indicated by - or +

Detailed processing logic is described below: 1.Read the referenceSexKaryotype from the header (e.g., "##referenceSexKaryotype=XY"), which determines the reference ploidy numbers for autosomes and sex chromosomes. Refer to the full sex ploidy reference table here: reference sex karyotype of ploidy caller. 2.For any whole chromosome \<DEL>/\<DUP> variant, calculate the ploidy difference for each sample based on the reference ploidy numbers and update the SNOM field accordingly. Use the sex chromosome ploidy reference for sex chromosomes.

An example ploidy VCF:

##referenceSexKaryotype=XY
##INFO=<ID=END,Number=1,Type=Integer,Description="End position of the variant described in this record">
##INFO=<ID=SVTYPE,Number=1,Type=String,Description="Type of structural variant">
##ALT=<ID=DEL,Description="Region of lowered copy number relative to the reference, or a deletion breakpoint">
##ALT=<ID=DUP,Description="Region of elevated copy number relative to the reference, or a tandem duplication breakpoint">
##FILTER=<ID=LowQual,Description="QUAL below 20">
##FORMAT=<ID=DC,Number=1,Type=Float,Description="Depth of coverage">
##FORMAT=<ID=NDC,Number=1,Type=Float,Description="Normalized depth of coverage">
#CHROM  POS ID  REF ALT QUAL    FILTER  INFO    FORMAT  SM-LGH3Z
chr1    1   .   N   .   28.8542 PASS    END=248956422   DC:NDC  62.6489:1.01177
chr2    1   .   N   .   31.4584 PASS    END=242193529   DC:NDC  61.938:1.00029
chr3    1   .   N   .   30.9953 PASS    END=198295559   DC:NDC  61.612:0.995028
chr4    1   .   N   .   21.6147 PASS    END=190214555   DC:NDC  60.5016:0.977094
chr5    1   .   N   .   31.0972 PASS    END=181538259   DC:NDC  61.6479:0.995607
chr6    1   .   N   .   31.4546 PASS    END=170805979   DC:NDC  61.8865:0.999461
chr7    1   .   N   .   31.0756 PASS    END=159345973   DC:NDC  61.6399:0.995478
chr8    1   .   N   .   29.7097 PASS    END=145138636   DC:NDC  61.3224:0.990351
chr9    1   .   N   .   31.1025 PASS    END=138394717   DC:NDC  61.6499:0.995639
chr10   1   .   N   <DEL>   31.3434 PASS    END=133797422   DC:NDC  62.0741:0.00249
chr11   1   .   N   <DEL>   31.4584 PASS    END=135086622   DC:NDC  61.9018:0.49708
chr12   1   .   N   <DUP>   31.1682 PASS    END=133275309   DC:NDC  62.1638:1.50394
chr13   1   .   N   <DUP>   20.9025 PASS    END=114364328   DC:NDC  60.4509:1.976276
chr14   1   .   N   .   31.1918 PASS    END=107043718   DC:NDC  62.1537:1.00378
chr15   1   .   N   .   26.9044 PASS    END=101991189   DC:NDC  62.884:1.01557
chr16   1   .   N   .   29.5543 PASS    END=90338345    DC:NDC  62.5433:1.01007
chr17   1   .   N   .   17.2853 LowQual END=83257441    DC:NDC  63.6241:1.02752
chr18   1   .   N   .   24.6182 PASS    END=80373285    DC:NDC  60.7381:0.980915
chr19   1   .   N   .   23.6804 PASS    END=58617616    DC:NDC  63.1802:1.02035
chr20   1   .   N   .   29.2849 PASS    END=64444167    DC:NDC  62.5859:1.01076
chr21   1   .   N   .   29.4056 PASS    END=46709983    DC:NDC  61.2726:0.989546
chr22   1   .   N   .   16.8285 LowQual END=50818468    DC:NDC  63.6517:1.02797
chrX    1   .   N   <DUP>   150 PASS    END=156040895   DC:NDC  88.8375:2.050044
chrY    1   .   N   <DUP>   150 PASS    END=57227415    DC:NDC  88.8375:2.050044

The resulted VCF:

#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO	FORMAT	SM-LGH3Z
chr10	1	.	N	<DEL>	31.3434	PASS	END=133797422;CTB=10p15.3-q26.3	DC:NDC:SNOM	62.0741:0.00249:-10,-10
chr11	1	.	N	<DEL>	31.4584	PASS	END=135086622;CTB=11p15.5-q25	DC:NDC:SNOM	61.9018:0.49708:-11
chr12	1	.	N	<DUP>	31.1682	PASS	END=133275309;CTB=12p13.33-q24.33	DC:NDC:SNOM	62.1638:1.50394:+12
chr13	1	.	N	<DUP>	20.9025	PASS	END=114364328;CTB=13p13-q34	DC:NDC:SNOM	60.4509:1.976276:+13,+13
chrX	1	.	N	<DUP>	150	PASS	END=156040895;CTB=Xp22.33-q28	DC:NDC:SNOM	88.8375:2.050044:+X
chrY	1	.	N	<DUP>	150	PASS	END=57227415;CTB=Yp11.32-q12	DC:NDC:SNOM	88.8375:2.050044:+Y

Resulted JSON:

{
  "header": {
    "annotator": "Illumina Connected Annotations 3.24.0",
    ...
    "samples": [
      "SM-LGH3Z"
    ]
  },
  "positions": [
    {
      "chromosome": "chr10",
      "position": 1,
      "svEnd": 133797422,
      "refAllele": "N",
      "altAlleles": [
        "<DEL>"
      ],
      "quality": 31.3434,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "10p15.3-q26.3",
      "samples": [
        {
          "simpleNomenclature": "-10,-10",
          "normalizedDepthOfCoverage": 0.0025
        }
      ],
      "variants": [
        ...
      ]
    },
    {
      "chromosome": "chr11",
      "position": 1,
      "svEnd": 135086622,
      "refAllele": "N",
      "altAlleles": [
        "<DEL>"
      ],
      "quality": 31.4584,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "11p15.5-q25",
      "samples": [
        {
          "simpleNomenclature": "-11",
          "normalizedDepthOfCoverage": 0.4971
        }
      ],
      "variants": [
        ...
      ]
    },
    {
      "chromosome": "chr12",
      "position": 1,
      "svEnd": 133275309,
      "refAllele": "N",
      "altAlleles": [
        "<DUP>"
      ],
      "quality": 31.1682,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "12p13.33-q24.33",
      "samples": [
        {
          "simpleNomenclature": "+12",
          "normalizedDepthOfCoverage": 1.5039
        }
      ],
      "variants": [
        ...
      ]
    },
    {
      "chromosome": "chr13",
      "position": 1,
      "svEnd": 114364328,
      "refAllele": "N",
      "altAlleles": [
        "<DUP>"
      ],
      "quality": 20.9025,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "13p13-q34",
      "samples": [
        {
          "simpleNomenclature": "+13,+13",
          "normalizedDepthOfCoverage": 1.9763
        }
      ],
      "variants": [
        ...
      ]
    },
    {
      "chromosome": "chrX",
      "position": 1,
      "svEnd": 156040895,
      "refAllele": "N",
      "altAlleles": [
        "<DUP>"
      ],
      "quality": 150,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "Xp22.33-q28",
      "samples": [
        {
          "simpleNomenclature": "+X",
          "normalizedDepthOfCoverage": 2.05
        }
      ],
      "variants": [
        ...
      ]
    },
    {
      "chromosome": "chrY",
      "position": 1,
      "svEnd": 57227415,
      "refAllele": "N",
      "altAlleles": [
        "<DUP>"
      ],
      "quality": 150,
      "filters": [
        "PASS"
      ],
      "cytogeneticBand": "Yp11.32-q12",
      "samples": [
        {
          "simpleNomenclature": "+Y",
          "normalizedDepthOfCoverage": 2.05
        }
      ],
      "variants": [
        ...
      ]
    }
  ],
  "samples": [
    {
      "id": "SM-LGH3Z",
      "simpleNomenclature": "48,XY,-10,-10,-11,+12,+13,+13,+X,+Y"
    }
  ]
}

References

• An International System for Human Cytogenomic Nomenclature (2020)
• HGVS website describing ISCN
• Illumina DRAGEN v4.3 Ploidy Caller
• Illumina DRAGEN v4.3 CNV Output