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:

Identify Variant Type: The algorithm recognizes several types of chromosomal variants such as duplications, deletions, copy number gains, and copy number losses.
Locate Cytogenetic Bands: Using the start and end positions of the variant, the algorithm identifies the corresponding cytogenetic bands on the chromosome.
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:

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

More examples:

Chromosome

Start Position

End Position

Variant Type

ISCN Notation

19200001

deletion

del(8)(p21.3)

19200001

duplication

dup(8)(p21.3)

19200001

135400001

deletion

del(8)(p21.3q24.23)

19200001

135400001

duplication

dup(8)(p21.3q24.23)

127300001

131500000

duplication

dup(8)(q24.21q24.22)

127300001

131500000

copy number gain

dup(8)(q24.21q24.22)

128746677

128749160

duplication

dup(8)(q24.21q24.21)

128746677

128749160

copy number gain

dup(8)(q24.21q24.21)

135400001

138900001

duplication

dup(8)(q24.23q24.3)

135400001

146364022

deletion

del(8)(q24.23)

135400001

145138635

duplication

dup(8)(q24.23q24.3)

135400001

138900001

copy number loss

del(8)(q24.23q24.3)

135400001

146364022

duplication

dup(8)(q24.23)

86200001

103700000

copy number loss

del(X)(q21.31q22.2)

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:

Chromosome
Genetic Band of the CNV
Start/End Position
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.
(Optional) Loss of Heterozygosity

An example input VCF line:

#CHROM

POS

REF

ALT

QUAL

FILTER

INFO

FORMAT

FEMALE_SAMPLE

47880199

DRAGEN:CNLOH:3:47880200:53573886

<LOH>

100

PASS

END=53573886;REFLEN=5693687

GT:SM:CN:BC:PE

1/1:1.0:2:5694:15,15

57801513

DRAGEN:GAINLOH:6:57801514-57827028

<LOH>

100

PASS

END=57827028;REFLEN=25515

GT:SM:CN:BC:PE

1/1:1.5:3:532812:15,15

133042524

DRAGEN:GAIN:X:133042525:136149357

<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

...

INFO

FORMAT

FEMALE_SAMPLE

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

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

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:

Reference Sex Karyotype, which is given in the input VCF header
Chromosome
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

REF

ALT

QUAL

FILTER

INFO

FORMAT

SM-LGH3Z

chr10

<DEL>

31.3434

PASS

END=133797422;CTB=10p15.3-q26.3

DC:NDC:SNOM

62.0741:0.00249:-10,-10

chr11

<DEL>

31.4584

PASS

END=135086622;CTB=11p15.5-q25

DC:NDC:SNOM

61.9018:0.49708:-11

chr12

<DUP>

31.1682

PASS

END=133275309;CTB=12p13.33-q24.33

DC:NDC:SNOM

62.1638:1.50394:+12

chr13

<DUP>

20.9025

PASS

END=114364328;CTB=13p13-q34

DC:NDC:SNOM

60.4509:1.976276:+13,+13

chrX

<DUP>

150

PASS

END=156040895;CTB=Xp22.33-q28

DC:NDC:SNOM

88.8375:2.050044:+X

chrY

<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

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