Multi-family Mendelian analysis

The Multi-family Mendelian analysis report builder returns the zygosity distribution across cases and controls (the number of homozygous, heterozygous, and compound heterozygous carriers) for each variant observed in the index case.

Multi-Family Mendelian Analysis in Sequence Miner

Example use case

Given an index case and a group of cases and controls, the user wishes to evaluate the variants observed in the index by measuring the distribution of homozygous, heterozygous, and compound heterozygous carriers of each variant across cases compared to controls.

Description of the algorithm

Variants are first filtered according to coverage and other user-defined settings. Variants are classified as homozygous, heterozygous or compound heterozygous for an index case and/or for multiple cases versus controls.

Interpreting the output

The output is a detailed report with annotation for every variant identified in the index case that meets the filtering criteria selected by the user (VEP_consequence, maxAf cutoffs for dominant and recessive models, maxGf for the recessive model, etc.). Annotation includes sample and data quality metrics, VEP, and diagnostic information.

Column descriptions

Basic columns and descriptions

Group	Column	Description
Basic
	Call	The actual called sequence (variant), found by replacing a part of the reference sequence and denoted by Pos and Reference, with the sequence in the Call column
	Chrom	he chromosome of the variant, represented as chr1, chr2, …, chr22, chrXY, chrX, chrY, chrM
	hetORhom	The zygosity of the call, either “het” or “hom”
	Pos	The (first) base pair position of the sequence variant, i.e., the position of the first nucleotide in the Reference column
	Reference	Sequence from the reference build; the first base starting at the base pair position in the Pos column

CGD columns and descriptions

Group	Column	Description
CGD		The CGD columns provide information for variants based on the manually curated database of variants associated with known medically significant conditions and available interventions (http://research.nhgri.nih.gov/CGD/)
	AGE_GROUP	Pediatric: less than 18 years of age; Adult: at least 18 years of age
	COMMENTS	Observations noted by curators
	CONDITION	Conditions resulting from mutations in the same gene but may otherwise be placed in the “General” Intervention category
	INHERITANCE	Pattern of inheritance: AD - autosomal dominant; AR - autosomal recessive; BG - blood group; Digenic - a condition resulting from simultaneous mutations in two different genes; Maternal - maternal mitochondrial inheritance; XL - X-linked (because X-linked conditions can frequently have manifestations in both genetic sexes, X-linked conditions are not designated as dominant or recessive)
	INTERVENTION_CATEGORIES	This category includes organ systems for which specific and additional interventions may be beneficial
	INTERVENTION_RATIONALE	Description of the intervention and its benefit
	MANIFESTATION_CATEGORIES	Includes organ systems affected by mutations in corresponding genes; recognition of involved organ systems may help guide supportive care
	REFERENCES	The PubMed ID (PMID) of the reference

Diag columns and descriptions

Group	Column	Description
Diag
	ACMGcat	Categorization of the sequence variants according to the ACMG scheme
	chz	This field is equal to 1 (true) if the index is/cases are compound heterozygous (CHZ) (see GENE_CHZinGene) and none of the controls are homozygous
	ChzAHet	CHZ with allelic heterogeneity (AHet); this field is equal to 1 (true) if the variant contributes to CHZ in a gene (not necessarily all the same variants) and is absent as a CHZ variant from controls (in males, the X chromosome is considered separately)
	Dom	Dominant variant; this field is equal to 1 (true) if the variant is present in cases and absent in control individuals
	DomAhet	Dominant variant considering allelic heterogeneity (AHet); this field is equal to 1 (true ) if variants in a gene (not necessarily the same variant) are present in cases (“f/m_subjWithVarInGene” > 1) and absent in control subjects (“f/m_CTRLs_subjWithVarInGene” = 0)
	HRec	Homozygous recessive variant; this field is equal to 1 (true) if the variant is homozygous in cases (or hemizygous in males for variants on the X chromosome) and no homozygous variants (or hemizygous variants on X in males) are present in controls
	HRecAHet	Homozygous recessive with allelic heterogeneity (AHet); this field is equal to 1 (true) if the variant is homozygous in cases, or males are hemizygous for variants on the X chromosome (not necessarily the same variant in all cases) and no homozygous variants (or hemizygous variants on X in males) are present in controls
	otherpos	For a particular CHZ variant, the basepair position of the other variant(s) that produces compound heterozygosity

EuroGenetest columns and descriptions

Group	Column	Description
EuroGenetest		The EuroGenetest columns are derived from a European Commission project database containing European genetic testing information for particular genes, variants, and diseases.
	Diseases	Diseases associated with a variant derived from the European Commission project database
	NoOfDiseases	Number of diseases associated with a variant derived from the European Commission project database
	NoOfpanels	Number of gene panels associated with a variant derived from the European Commission project database
	panels	EuroGenetest panels associated with a variant derived from the European Commission project database

Female columns and descriptions

Group	Column	Description
female		In the female group, the following columns are repeated for fCASEs and fCTRLs.
	GeneCovered	The number of subjects (within the given male/female and case/control category) that have at least 8 reads (depth >=8) at the position of all the variants in a given gene
	subjCompHeterInGene	The number of subjects (within the given male/female and case/control category) who are potentially compound heterozygous in a given gene. Note that the variants are not phased based on parent of origin; an individual need only have a single homozygous variant or two heterozygous variants in a given gene to be classified as CHZ
	subjWithHomVar:	The number of subjects (within the given male/female and case/control category) homozygous for the given variant
	subjWithHomVarInGene	The number of subjects (within the given male/female and case/control category) with homozygous variants in the gene
	subjWithVar	The number of subjects (within the given male/female and case/control category) with the variant
	subjWithVarInGene	The number of subjects (within the given male/female and case/control category) with any variant in the gene
	varCovered	The number of subjects (within the given male/female and case/control category) that have at least 8 reads at the variant position

Gene columns and descriptions

Group	Column	Description
Gene
	Aliases	The aliases of the given gene
	avg_depth	The average sequence read depth in the exome of the given gene
	exomeSize	The sum of the base pair size of all the exons in the gene
	exontype	The type of exon (“coding” or “noncoding”)
	lt10	The fraction of the exome with sequence read coverage less than 10X
	lt15	The fraction of the exome with sequence read coverage less than 15X
	lt20	The fraction of the exome with sequence read coverage less than 20X
	lt25	The fraction of the exome with sequence read coverage less than 25X
	lt30	The fraction of the exome with sequence read coverage less than 30X
	lt5	The fraction of the exome with sequence read coverage less than 5X
	maximum_allele_freq_for_dominant
	maximum_allele_freq_for_recessive
	maximum_genotype_freq_for_recessive
	MOI	Mode of inheritance
	Paralogs	The paralogs of the given gene
	RmaxAf	Maximum allele frequency to use for recessive alleles set as input parameter
	RmaxGf	Maximum gene frequency to use for recessive disorders set as input parameter
	Symbol	Based on HGNC when it exists, otherwise it is the Ensembl internal alias

GO columns and descriptions

Group	Column	Description
GO
	Descriptions	Gene ontology descriptions
	IDs	Gene ontology identifiers

GT columns and descriptions

Group	Column	Description
GT
	CallCopies	Because the focus is only on variants from the reference, CallCopies refers to how many copies of the variant exist in a subject; a CallCopies value of 2 therefore corresponds to a homozygous variant, whereas a CallCopies value of 1 corresponds to a heterozygous variant
	CallRatio	Proportion of reads containing the variant call; expected to be close to 0.5 for heterozygous calls and close to 1 for homozygous calls
	Depth	The number of reads used for evaluating the corresponding call
	FILTER	Quality parameter using the ratio between gt-quality and depth, showing if the call is considered “LowQual” quality (not useable) or “PASS”; this remains a crude quality measure
	formatZip	VCF genotype field
	FS	Fisher’s exact test of read strand; f the reference reads are balanced between forward and reverse strands, then the alternate reads should be as well
	GL_Call	A statistical measure indicating the likelihood that the call is wrong; the scale has been converted to use only integer numbers - the higher the number, the less likely it is that the call is wrong
	vcf_alt	Alternate (variant) nucleotide sequence as reported in the vcf
	vcf_pos	Coordinate (position) of the reference nucleotide sequence

KNOWN columns and descriptions

Group	Column	Description
KNOWN		The KNOWN columns provide publicly available information about the candidate gene and/or variant.
	distance	The distance between a known variant and the identified variant
	exactMatch	A Boolean column (1/0) indicating if the variant is a known variant (instead of near a known variant, or a at the same position with a different call allele)
	Gene_diseases	Diseases known to be associated with the gene
	Gene_Symbol	Based on HGNC when it exists, otherwise it is the Ensembl internal alias
	GeneLists	Gene list membership of the gene in which the variant is found
	pmid	PubMed ID of the reference from which the information was obtained
	var_diseases	Diseases known to be associated with the variant

Male columns and descriptions

Group	Column	Description
male		In the male group, the following columns are repeated for mCASEs and mCTRLs.
	GeneCovered	The number of subjects (within the given male/female and case/control category) that have at least 8 reads (depth >=8) at the position of all the variants in a given gene
	subjCompHeterInGene	The number of subjects (within the given male/female and case/control category) who are potentially compound heterozygous in a given gene. Note that the variants are not phased based on parent of origin; an individual need only have a single homozygous variant or two heterozygous variants in a given gene to be classified as CHZ
	subjWithHomVar	The number of subjects (within the given male/female and case/control category) homozygous for the given variant
	subjWithHomVarInGene	The number of subjects (within the given male/female and case/control category) with homozygous variants in the gene
	subjWithVar	The number of subjects (within the given male/female and case/control category) with the variant
	subjWithVarInGene	The number of subjects (within the given male/female and case/control category) with any variant in the gene
	varCovered	The number of subjects (within the given male/female and case/control category) that have at least 8 reads at the variant position

OMIM columns and descriptions

Group	Column	Description
OMIM		The OMIM columns provide the OMIM-designated identification for a particular gene and related disease description
	Descriptions	OMIM disease descriptions for the gene
	IDs	The OMIM ID(s) of the gene

VEP columns and descriptions

Group	Column	Description
VEP		The VEP (Variant Effect Predictor) columns provide functional annotations for variants based on the ENSEMBL SNP Effect Predictor database. For more information, visit the VEP web page: http://www.ensembl.org/info/docs/tools/vep/index.html/.
	CDS_position	Position of the base pair in the coding sequence; a value is given for each transcript
	Max_Af	Maximum allele frequency from public databases (1000Genomes, Exome Variant server, etc.)
	max_consequence	Consequence type reported for this variant having the greatest impact
	Max_Impact	Classification of the level of severity of the transcript consequence type assigned by VEP
	Max_Score	Maximum score for the variant as observed in dbNSFP [Score=max ((1-Sift_score), Polyphen2_HDIV_score, Polyphen2_HVAR_score)]
	Protein_Position	Position of the amino acid in the protein sequence (only if the variant falls within a coding sequence); a value is given for each corresponding transcript specified in the CDS position field
	Transcript_count	Number of different transcripts in which the variant is found

Other columns and descriptions

Group	Column	Description
Other columns
	Amino_Acids	The amino acid with and without variant (provided only if the variation affects the protein-coding sequence), otherwise “.”
	Biotype	Biological class of transcript or regulatory feature
	CLINICAL_SIGNIFICANCE	The clinical significance (e.g., pathogenic, benign, unknown significance, drug-response, risk factor, etc.) of the variant as annotated (commented) by users. If the same variant has several comments, this cell will contain a set of values
	MODE_OF_INHERITENCE	The user-annotated (commented) mode of inheritance of the variant; if the same variant has several comments, this cell will contain a set of values
	Refgene	The accession number from NCBI of the affected transcripts
	TEXT	The description (comment) component for the user’s annotation of the variant

Perspective views

Perspectives subtabs focus on subsets of the columns in the Default view.

Perspectives

Perspective	Description
Default view
Dominant
Recessive

Drill-in reports

Drill-in reports

Drill in	Description
CHZforVar	This drill-in report lists all compound heterozygous variants that include the selected gene variant
CHZforGene	This drill-in report lists all compound heterozygous variants that reside in the same gene as the selected gene variant
AllWithVar	This drill-in report lists all carriers among the cases and controls of the selected variant
AllVarsInGene	This drill-in report lists all carriers among the cases and controls of the selected variant or of variants in the same gene as the selected variant