About


This server performs cosegregation analysis by the Full-Likelihood method [1] and outputs a Bayes factor that can be integrated into the variant classification guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP).


The website is designed for classifying variants in a known disease gene as pathogenic or benign within the context of clinical genetic testing. If you want to conduct cosegregation analysis for gene discovery research, i.e., to find out which gene associates with the disease of interest, then please see my other package VICTOR.



Quick start


Click on the “ANALYSIS” tab, provide a gene symbol and upload a pedigree file, then click the “Submit” button.



Pedigree File


The Pedigree File must be a tab- or space-delimited text file. If you edit data in Excel, please save as “Tab delimited Text (.txt)”. Missing values are represented by a period. Empty fields, space within fields, or quoted fields are not allowed. IDs are case-sensitive with alphanumeric characters or the _ character.


Required columns:

PedID: Pedigree_ID. Alphanumeric. It cannot be 0. Multiple pedigrees are allowed.

IndID: Individual_ID. Alphanumeric. It cannot be 0. IndID does not need to be unique across pedigrees.

Father: Individual_ID of father. Put 0 for founders. If one parent is 0, both parents must be 0.

Mother: Individual_ID of mother. Put 0 for founders. If one parent is 0, both parents must be 0.

Sex: Biological sex, not the personal identification of one's own gender. 0=UnknSex, 1=M=Male, 2=F=Female.

Aff*: Affection status. Value is UnknAff (unknown), Unaff (unaffected), or a disease name.

Age: Age-of-onset for affected and age-of-the-last-exam for unaffected individuals. 0 for unknown age.

FPTP: The first person tested positive for the variant in each pedigree. 1 for FPTP; 0 for others.

Geno: Genotype. 0=unknown, neg=negative, het=heterozygous-carrier, hom=homozygous-carrier. You don’t need to input genotype for obligatory carriers as the program will infer automatically. You don’t need to input negative genotype (non-carrier) for spouses even if you assume that the variant enters the pedigree only once. The program will fill in the genotype based on allele frequency.


Optional columns:

Twin: Twin status. 0: not twin; positive integer: siblings with the same number are twins.

Pop: Population. This column overrides the advanced option "Population" on the webpage.

Cohort: Year range. This column overrides the advanced option "Year range" on the webpage.

Comment: Information to be shown in pedigree drawings.


* For cancer-associated genes, Aff is the first diagnosis of any cancer. Below is a list of strings for the “Aff”:

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Name    Descriptions

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unaff   unaffected

Lip     Lip

Tongue  Tongue

Mouth   Mouth

Oral    Oral cavity (lip, tongue, mouth)

Saliv   Salivary gland

Parotid Parotid gland

Tonsil  Tonsil

Oroph   Oropharynx

Nasoph  Nasopharynx

Pyrifm  Pyriform sinus

Hypoph  Hypopharynx

Pharynx Pharynx (include Oropharynx, Nasopharynx, Hypopharynx, Pharynx unspecified)

BCP     Buccal cavity and pharynx (include Lip, Tongue, Mouth, Saliv, Parotid, Tonsil, Pharynx)

Throat  Oropharynx, Tonsil, Base of tongue

Nasal   Nasal cavity and middle ear

A.sinus Accessory sinuses

Larynx  Larynx

Trachea Trachea

Oesoph  Oesophagus

Stomach Stomach (synonym: Gastric)

SmBowel Small intestine

Colon   Colon

RS.junc Rectosigmoid junction

Rectum  Rectum

CRC     Colorectal cancer (include Colon, RS.junc, Rectum)

Anus    Anus

Liver   Liver

Gall    Gallbladder

Biliary biliary tract

PanCa   Pancreas

BilPan  biliary tract and Pancreas

Lung    Lung

Thymus  Thymus

Heart   Heart

Bone    Bone

Bone.l  Bone of limbs

Bone.o  Bone other than limbs

Osteo   Osteosacoma

Sarcoma Soft tissue sarcoma and bone sarcoma

CM      Cutaneous Melanoma

NM.skin Non-melanoma of skin

Meso    Mesothelioma

STS     Soft-tissue sarcoma (Mesothelioma, Kaposi, Peripheral nerves, Peritoneum & retroperitoneum, Connective & soft tissue)

BrCa    Breast

Vagina  Vagina

Cervix  Cervix uteri

Corpus  Corpus uteri

Uterus  Cervix or corpus uteri

OvCa    Ovary

Penis   Penis

ProCa   Prostate

Testis  Testis

UpUrin  Upper Urinary tract malignancy (kidney and renal pelvis)

Kidney  Kidney

RenalCC Renal Cell Carcinoma (only for CI5-XI, a subset of UpUrin)

RCC     Renal Cell Carcinoma (only for CI5-XI, a subset of UpUrin)

Ureter  Ureter

Bladder Bladder

Urinary Urinary tract (include Kidney, Renal pelvis, Ureter, Bladder, Other urinary organs)

Eye     Eye

UM      Uveal melanoma

Mening  Meninges

CNS     Central nervous system

Brain   Brain

Thyroid Thyroid

MTC     Medullary Thyroid Cancer

Adrenal Adrenal gland

Hodgkin Hodgkin lymphoma

NH.lym  Non-Hodgkin lymphoma

IPD     Immunoproliferative diseases

Myeloma Multiple myeloma

L.leuk  Lymphoid leukemia

M.leuk  Myeloid leukemia

U.leuk  Cell-unspecified leukemia

Leuk    Leukemia

Lymph   Lymphoid Neoplasms (include Hodgkin lymphoma, Non-Hodgkin lymphoma, MALT-lyphoma, Lymphoid leukaemia)

------------------------------------------------------------------------------------------------------------------------



Below is an example Pedigree File and a drawing for BRCA1. Please note that affection status for analysis depends on the gene. Because the liability class model for BRCA1 involves only breast, ovarian, and pancreatic cancer, individual 6 (prostate cancer) and 17 (lung cancer) are “unaffected”. Therefore, the squares for these two persons are not filled with solid black color. Also note that the proband, individual 17, is not affected. This is correct as the definition of proband is the first person who tested positive for the variant.


PedID IndID Father Mother Sex Aff    Age Geno FPTP

ped1  1     0      0      M   .      79  .    0

ped1  2     0      0      F   .      78  .    0

ped1  3     1      2      F   BrCa   40  .    0

ped1  4     1      2      F   unaff  100 .    0

ped1  5     1      2      F   BrCa   85  .    0

ped1  6     1      2      M   ProCa  43  .    0

ped1  7     0      0      M   unaff  80  .    0

ped1  8     7      3      M   unaff  73  .    0

ped1  9     7      3      M   unaff  41  .    0

ped1  10    0      0      F   .      89  .    0

ped1  11    7      3      M   PanCa  30  Het  0

ped1  12    0      0      F   unaff  80  .    0

ped1  13    9      10     F   BrCa   41  Het  0

ped1  14    9      10     M   unaff  60  .    0

ped1  15    9      10     F   BrCa   50  Het  0

ped1  16    9      10     F   unaff  60  Het  0

ped1  17    11     12     M   Lung   49  Het  1

ped1  18    11     12     F   unaff  38  .    0

ped1  19    11     12     M   unaff  36  Het  0

ped1  20    11     12     F   OvCa   48  Het  0



References

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  1. 1.Thompson D, Easton DF, Goldgar DE. A Full-Likelihood Method for the Evaluation of Causality of Sequence Variants from Family Data. The American Journal of Human Genetics. 2003;73(3):652-655.

  2. 2.Kuchenbaecker KB et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416. PMID:28632866.

  3. 3.Antoniou AC et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98(8):1457-66. PMID:18349832.

  4. 4.Mocci E et al. Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. Cancer Epidemiol Biomarkers Prev. 2013;22(5):803-11. doi: 10.1158/1055-9965.EPI-12-0195. PMID:23456555.

  5. 5.BOADICEA V7 Release 114.

  6. 6.Belman et al. Considerations in assessing germline variant pathogenicity using cosegregation analysis. Genetic in Medicine. 2020