Abstract
In one sentence: this is a normal male microarray with no missing or extra chromosomal material, whose only additional finding — long runs of identical DNA (AOH) — is an expected, benign consequence of the parents being first cousins.
Chromosomal microarray on DNA from uncultured peripheral blood returned arr(X,Y)x1,(1-22)x2 — a normal male dosage result, the array equivalent of a 46,XY karyotype. The SNP component of the array identified multiple long contiguous regions of absence of heterozygosity (AOH) spanning 10.4% (288.2 Mb) of the haploid genome across 12 autosomes.
AOH is not a copy-number abnormality and not a disease. It is a marker of shared ancestry between the parents (here, reported first cousins): the subject inherited stretches of DNA that are identical from both sides. The laboratory explicitly notes this pattern "can be observed in normal individuals," is "typically associated with common descent," and is "not diagnostic." Its only forward-looking significance is a modestly raised prior that, if a recessive condition were clinically suspected, a causative homozygous variant might lie inside one of these regions.
A normal 46,XY male with genome-wide autozygosity from parental consanguinity. Benign, non-progressive, seen in healthy people.
Not an abnormal copy number, not a syndrome, not a diagnosis, not a measure of intelligence, and not uniparental disomy.
Only relevance is reproductive: a slightly higher prior for autosomal-recessive conditions, addressed by genetic counselling.
The Result, Decoded
The ISCN string looks cryptic but says something reassuringly simple. Read left to right, it is just the sex chromosomes at one copy each and every autosome at the normal two copies.
= male sex chromosomes
autosome (normal dosage)
no deletions · no duplications
Reading the notation: arr = result from a microarray. (X,Y)x1 = a single copy each of X and Y (a normal male). (1-22)x2 = the expected two copies of chromosomes 1 through 22. There is no "+", "-", "del" or "dup" anywhere in the string, which is precisely why the copy number is normal. The array measures dosage and SNP genotype, not banded structure, so it cannot by itself see a balanced translocation — but for chromosome number and dosage, this is a clean normal male.
AOH Region Atlas
Twelve autosomes carry runs of absence of heterozygosity. Below, each involved chromosome is drawn to scale (hg19 lengths), with its centromere marked and every AOH block painted in the teal accent at its true position. The 20-row region table follows.
Region table · 20 AOH blocks
| Chr | Cytoband | Start (hg19) | End (hg19) | Size (Mb) | Relative size | Candidate genes |
|---|---|---|---|---|---|---|
| Total AOH | 288.21 | = lab-reported 288.2 Mb (rounding-consistent) | ||||
Autozygosity & the Inbreeding Coefficient
The fraction of the genome sitting in runs of homozygosity is an empirical estimator of the inbreeding coefficient, FROH. Here it is 288.2 / 2,881 = 0.100 (10.0%).
Autozygous fraction of the genome
Autosomal haploid length ≈ 2,881 Mb. AOH = 288.2 Mb → FROH = 10.00%. This is an empirical genomic estimator of the inbreeding coefficient F, not a pedigree-expected value.
Relationship ladder — where F ≈ 0.10 lands
Observed F ≈ 0.10 sits between the first-cousin expectation (0.0625) and the double-first-cousin / uncle–niece tier (0.125), and far below full-sib / parent–child (0.25).
A single first-cousin loop predicts F = 0.0625. The observed ≈0.0375 excess is best read as additional background relatedness — first cousins whose own ancestors were themselves related (an endogamous lineage), giving an effective parental kinship coefficient near 0.10. Caveat: FROH carries sampling variance, and a single relationship slightly closer than first cousins could also yield ≈0.10; the excess is suggestive of background consanguinity, not proof of it.
Segment Length & Recency
Long, unbroken blocks are the signature of recent shared ancestry — recombination has not yet had generations to chop them up. Essentially 100% of this genome's AOH is in long (≥5 Mb) segments, with no short-segment background tail.
The 20 AOH blocks, sorted by size (Mb)
AOH burden per chromosome (Mb)
At ~1 cM/Mb, the expected mean IBD segment is ~50/g Mb where g is the number of meioses back to the shared ancestor. A mean of 14.4 Mb implies g≈3–4; the 42 Mb chr18 tract implies g≈1, i.e. an almost-uninterrupted path. Both point to relatedness within the last few generations, not ancient population drift.
UPD confines homozygosity to a single chromosome or one terminal segment. Here AOH is scattered as 20 interstitial blocks across 12 chromosomes, none homozygous end-to-end. That multi-chromosome scatter is the definitive fingerprint of consanguinity — each block an independent identity-by-descent tract — and excludes UPD.
Candidate Gene Map
Within each AOH interval, recessive-disease genes are worth noting because a homozygous pathogenic variant, if present, would most plausibly reside here. These are screening candidates only — not diagnoses. Genes flagged PHENO overlap the subject's reported features (macrocephaly, polydactyly, short stature, prominent nose).
Presence of a gene inside an AOH block means only that the region is homozygous, not that the gene is mutated. The array does not sequence these genes. None of the entries below is a diagnosis. The definitive next step, only if a specific recessive disorder is clinically suspected, is targeted exome/genome sequencing prioritized to these AOH intervals. Dominant/de-novo genes (e.g. GLI3, PTEN, CHD8, NSD1) are listed for phenotype context but are not made more likely by autozygosity.
BBS9 (7p14.3, AR Bardet-Biedl) & GLI3 (7p14.1, Greig CPS) — postaxial polydactyly + macrocephaly.
MPDZ (9p23, AR hydrocephalus), ASPA (17p13, Canavan), MAN2B1 (19p13, α-mannosidosis).
OBSL1 (2q35, 3-M), DYM (18q21, Smith-McCort, normal IQ), PROP1/GHRHR (CPHD).
CFTR (7q31.2) sits in an AOH block — warrants CF carrier screening; does not explain dysmorphism.
Clinical Interpretation & Record Accuracy
The microarray found no chromosomal cause for the presentation and does not, by itself, label the subject with any condition. The forward-looking issue is reproductive, not personal.
This CMA reports a normal male dosage result — two copies of every autosome plus one X and one Y, equivalent to 46,XY. No deletions, no duplications. The only additional observation is SNP-based AOH totaling 10.4% (288.2 Mb), a well-recognized, expected consequence of parental consanguinity that the lab states "can be observed in normal individuals" and is "not diagnostic." AOH is a marker of shared parental ancestry, not a disease.
The reported phenotype (macrocephaly, prominent nose, prior postaxial polydactyly, large hands, short stature, psychiatric presentation) in the setting of consanguinity and a family history of intellectual disability is compatible with a possible autosomal-recessive condition — but the microarray neither confirms nor excludes one. The subject is a high-functioning, intelligent adult; the left-cerebellar arachnoid cyst on MRI is described as incidental. Genetic counselling was appropriately offered, primarily for reproductive risk.
The psychiatry discharge summary from the admitting psychiatrist, FMC Inpatient Psychiatry Unit 22 characterizes this microarray as "abnormal." The underlying laboratory report does not support that characterization. The CMA identified no clinically relevant copy-number imbalances (a normal male result). The only additional observation was AOH, which the laboratory explicitly notes "can be observed in normal individuals," is "typically associated with common descent," and is "not diagnostic." Labeling the whole study "abnormal" conflates a normal dosage result with an incidental consanguinity marker. A precise description is: "Normal male copy-number microarray with incidental AOH consistent with consanguinity; not diagnostic." This note corrects the record for accuracy and asserts no clinical opinion beyond the lab report's own contents.
Reassurance points
- Copy number is normal — no missing/extra material, a normal male (46,XY-equivalent) result.
- AOH is not a disease; it marks parental common ancestry and is seen in healthy people. The lab calls it "not diagnostic."
- This test found no chromosomal cause for the presentation and does not label the subject with any condition.
- The finding is not fatal, not progressive — it does not predict deterioration.
- The MRI arachnoid cyst is described as incidental.
Recommended next steps
- No further genetic testing is required on the basis of this CMA alone — copy number is normal.
- If a specific recessive disorder is suspected, consider exome/genome sequencing targeted to the AOH regions.
- Refer to clinical genetics for phenotype-driven assessment, plus tests CMA cannot do (repeat-expansion, methylation).
- Genetic counselling for reproductive risk, ideally pre-conception, with expanded carrier screening for both prospective parents.
- Correct the medical record to describe the microarray accurately rather than as "abnormal."
Ancestry & Historical Context
An FROH of ≈0.10 tells a clear, unremarkable story: descent from a recent close-kin union within a somewhat endogamous lineage — the normal genetic signature of roughly a tenth of living humanity. It describes how the family married, not where on Earth they came from.
Tutankhamun (child of full siblings) reached F≈0.25 and was frail and disabled; Charles II of Spain, the terminal Habsburg, reached F≈0.254 through generations of uncle–niece and cousin unions and suffered compounded genetic disease that ended a dynasty. This subject sits at roughly four-tenths of those coefficients — a completely different, benign zone that hundreds of millions of healthy people occupy.
The F-ladder through history
| Individual / union | F | Outcome |
|---|
Charles Darwin married his first cousin Emma Wedgwood (1839); the Darwin–Wedgwood families were closely intermarried across generations. Three of their sons — George, Francis and Horace — became Fellows of the Royal Society and were knighted. A consanguineous background and exceptional cognitive accomplishment sit together without tension.
Postaxial polydactyly (extra little-finger-side digit) is among the most common human congenital traits — ~10× more frequent in people of African descent (~1 in 143 vs ~1 in 1,300–3,000 in Europeans), usually a benign autosomal-dominant trait, cleanly removed, with zero bearing on cognition.
Genome-wide long ROH reveals lineage structure — recent close kinship plus endogamy — but does not pin down a specific ethnicity, nationality, or geographic origin. That would require ancestry-informative markers, a separate analysis. The defensible statement from this data alone: recent close-kin marriage on an endogamous background — nothing more, nothing less.
Methods & Limitations
Assay & provenance
- Platform: Illumina Infinium CytoSNP-850K v1.2 BeadChip (copy number + SNP genotype / AOH).
- Specimen: DNA from uncultured peripheral blood.
- Accession: 22GS-140G00010.
- Collected: 2022-05-19 · Received: 2022-05-20 · Reported (orig.): 2022-06-01.
- Laboratory: Genetics & Genomics South Laboratory, Alberta Children's Hospital, Calgary.
- Ordered by: the admitting psychiatrist, FMC Inpatient Psychiatry Unit 22.
The report does not print the reference build. GRCh37/hg19 is assumed, which was standard for CytoSNP-850K clinical reporting in this era; GRCh38 adoption in routine clinical CMA lagged well past 2022. Every gene coordinate here was re-verified against Ensembl GRCh37 and UCSC hg19 cytoBand — all returned assembly GRCh37, with no build mismatch. All positions are therefore hg19.
What CMA cannot show
- Intelligence / cognition — CMA does not measure IQ.
- Psychiatric diagnoses — cannot diagnose or explain any psychiatric condition.
- Single-gene point mutations / small indels — needs exome/genome or targeted sequencing.
- Triplet-repeat expansions (Fragile X, Huntington) — need repeat-sizing assays.
- Methylation / imprinting defects (Prader-Willi/Angelman) — need methylation testing.
- Balanced rearrangements — translocations/inversions have no copy-number change and are invisible.
- Ancestry / ethnicity — AOH indicates shared descent, not a specific origin.
- Low-level mosaicism below the array's detection threshold.
Verification: 20 blocks re-summed to 288.21 Mb (lab-reported 288.2, rounding-consistent); FROH = 288.2/2,881 = 10.00%. Two candidate genes were removed on re-check — TRAM1 (actually chr8, wrong chromosome) and GLP2R (falls ~119 kb outside the 17p interval).
References
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- Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Entries cited inline (e.g. BBS9 #615986; GLI3/Greig #175700; CFTR/CF #219700; polydactyly PAPA1 #174200). https://omim.org
- Ensembl GRCh37 REST & UCSC hg19 cytoBand. Gene coordinates and cytobands verified against grch37.rest.ensembl.org and the UCSC Genome Browser.