X-linked disorders are caused by variants in genes on the X chromosome. Because males have only one X, X-linked recessive disorders affect mostly males, pass through unaffected carrier mothers and are never transmitted from father to son: every daughter of an affected man is an obligate carrier, and each son of a carrier mother has a 50% risk. In X-linked dominant disorders, an affected father passes the trait to all of his daughters and none of his sons, and an affected mother to half of her children. Review books list Duchenne and Becker muscular dystrophy, hemophilia A and B, G6PD deficiency, Bruton agammaglobulinemia, Wiskott-Aldrich syndrome, Fabry disease, Hunter syndrome, Lesch-Nyhan syndrome and OTC deficiency as X-linked recessive and hypophosphatemic rickets, fragile X syndrome, Rett syndrome and incontinentia pigmenti as X-linked dominant, although MedlinePlus now labels several of them (G6PD deficiency, Fabry disease, OTC deficiency, X-linked hypophosphatemia) simply X-linked.
Step-by-step pedigree flowchart
Step 1. Look for male-to-male transmission. A father gives his son a Y chromosome, never his X.
- Present: not X-linked. Think autosomal dominant (both sexes, every generation) or, rarely, Y-linked (only males, passed to every son).
- Absent: go to step 2.
Step 2. Who is affected?
- Mostly males, connected through unaffected women, with skipped generations: X-linked recessive (XLR).
- Both sexes in every generation, with more affected females than males: X-linked dominant (XLD).
Step 3. Test an affected father. He passes his X to every daughter and his Y to every son.
- XLR: all daughters are obligate carriers; no sons are affected.
- XLD: all daughters are affected; no sons are affected.
Step 4. Test a heterozygous mother.
- XLR carrier: each son has a 50% risk of being affected; each daughter a 50% chance of being a carrier.
- XLD: each child, son or daughter, has a 50% risk.
Step 5. Rule out the look-alikes.
- Autosomal dominant: 50% risk to each child regardless of sex, and male-to-male transmission can occur.
- Autosomal recessive: both sexes equally, usually one sibship with unaffected parents; see the autosomal recessive pedigree guide.
- Mitochondrial: passed only by mothers, potentially to all of their children; an affected father passes it to none.
Step 6. Explain an affected female in an XLR family: skewed X-inactivation (a manifesting carrier), a single X (Turner syndrome, 45,X), or an affected father plus a carrier mother.
| Parents | Sons | Daughters |
|---|---|---|
| XLR: affected father × unaffected mother | None affected | All carriers |
| XLR: carrier mother × unaffected father | 50% affected | 50% carriers |
| XLR: carrier mother × affected father | 50% affected | 50% affected, 50% carriers |
| XLD: affected father × unaffected mother | None affected | All affected |
| XLD: heterozygous mother × unaffected father | 50% affected | 50% affected |
Lyonization and skewed X-inactivation
- Early in embryonic life, one X in each female cell is inactivated at random (the Lyon hypothesis), and the same X stays inactive in all descendant cells. The XIST gene triggers it. When a cell has extra X chromosomes, all but one are inactivated, so the number of Barr bodies equals the number of X chromosomes minus one.
- Every heterozygous woman is therefore a mosaic. If inactivation is skewed toward silencing the normal X, a "carrier" develops disease: MedlinePlus notes that many women heterozygous for G6PD deficiency or OTC deficiency are affected much like men because of skewed X-inactivation.
- Manifesting carriers to know: Duchenne carriers (milder weakness and cramps, plus a raised risk of cardiomyopathy), Fabry disease (often symptomatic), OTC deficiency and G6PD deficiency.
- Labels are blurring. MedlinePlus now calls G6PD deficiency, Fabry disease, OTC deficiency, X-linked hypophosphatemia and X-linked Alport syndrome simply "X-linked", a label some experts prefer because many are not clearly dominant or recessive; review books, and the tables below, still sort them into recessive and dominant lists.
X-linked recessive disorders list
| Disorder | Gene (protein) | Classic clue |
|---|---|---|
| Duchenne muscular dystrophy | DMD (dystrophin): frameshift or nonsense variant, no dystrophin | Boy in early childhood with Gowers sign, calf pseudohypertrophy, very high CK, later dilated cardiomyopathy |
| Becker muscular dystrophy | DMD: in-frame variant, reduced or abnormal dystrophin | Same pattern, but onset in later childhood or adolescence and milder |
| Hemophilia A / B | F8 (factor VIII) / F9 (factor IX) | Hemarthroses and deep bleeding; prolonged PTT with normal PT and platelet count (hemophilia A vs B) |
| G6PD deficiency | G6PD | Hemolysis after infection, oxidant drugs (primaquine, dapsone, sulfonamides) or fava beans; Heinz bodies, bite cells (G6PD deficiency) |
| Bruton agammaglobulinemia | BTK (Bruton tyrosine kinase) | Very few or no B cells, all immunoglobulins low, bacterial infections once maternal IgG wanes (Bruton memory palace) |
| Wiskott-Aldrich syndrome | WAS (WASp) | Eczema, thrombocytopenia with small platelets, recurrent infections |
| X-linked SCID | IL2RG (common gamma chain) | No T or NK cells; severe infections, thrush and failure to thrive in infancy |
| Chronic granulomatous disease, X-linked form | CYBB (NADPH oxidase) | Catalase-positive infections, granulomas, abnormal DHR test; other genes cause autosomal recessive CGD |
| Fabry disease | GLA (alpha-galactosidase A) | Burning hand and foot pain, angiokeratomas, hypohidrosis, proteinuria, LVH (Fabry disease question) |
| Hunter syndrome (MPS II) | IDS (iduronate 2-sulfatase) | Coarse face, airway narrowing, hepatosplenomegaly, no corneal clouding |
| Lesch-Nyhan syndrome | HPRT1 (HGPRT) | Hyperuricemia, gout, dystonia, self-injury such as lip and finger biting |
| OTC deficiency | OTC (ornithine transcarbamylase) | Hyperammonemia in a newborn boy, high orotic acid, low BUN |
| Menkes disease | ATP7A (copper transporter) | Sparse kinky hair, failure to thrive, hypotonia, seizures, neurodegeneration |
| Ocular albinism type 1 | GPR143 | Poor visual acuity and nystagmus with normal skin and hair color |
| Red-green color blindness | OPN1LW, OPN1MW (cone opsins) | About 1 in 12 males of Northern European ancestry |
| Androgen insensitivity syndrome | AR (androgen receptor) | 46,XY with female external genitalia, undescended testes, no uterus, sparse pubic hair |
X-linked dominant disorders
| Disorder | Gene and mechanism | Classic clue |
|---|---|---|
| X-linked hypophosphatemia (hypophosphatemic rickets) | PHEX variant → high FGF23 → renal phosphate wasting | Rickets with low phosphate, bowed legs, short stature, dental abscesses; women affected about as much as men |
| Fragile X syndrome | FMR1 CGG repeat above 200 → gene silenced | Intellectual disability, long narrow face, large ears, enlarged testes after puberty; males more severe, about a third of affected females have intellectual disability |
| Rett syndrome | MECP2; over 99% have no family history | A girl develops normally for 6-18 months, then loses purposeful hand use, with hand-wringing, seizures and breathing problems (about three-quarters develop microcephaly); affected boys often die in infancy |
| Incontinentia pigmenti | IKBKG (NEMO); usually lethal early in development in males | Blisters → wart-like lesions → swirled hyperpigmentation → pale lines; few or small teeth, alopecia, nail changes, vision loss from abnormal blood vessels |
| Alport syndrome, X-linked form | COL4A5 (type IV collagen); about two-thirds of Alport cases | Hematuria → CKD, sensorineural hearing loss, anterior lenticonus; heterozygous women usually have hematuria only |
How sources classify them:
- Fragile X: MedlinePlus Genetics calls it X-linked dominant, since one full mutation can cause features in a female. It is also tested as a trinucleotide-repeat disorder: a mother's premutation (55-200 repeats) can expand past 200 in her eggs, while a father's premutation does not. Premutation carriers risk FXTAS and primary ovarian insufficiency. More in the fragile X guide.
- Hypophosphatemic rickets and Alport syndrome: Merck uses familial rickets and hereditary nephritis as its X-linked dominant examples; MedlinePlus now labels both simply X-linked.
The classic mnemonic (a memory aid, not the full list)
"Oblivious Female Will Often Give Her Boys Her x-Linked Disorders" = OTC deficiency, Fabry disease, Wiskott-Aldrich syndrome, Ocular albinism, G6PD deficiency, Hunter syndrome, Bruton agammaglobulinemia, Hemophilia A and B, Lesch-Nyhan syndrome, Duchenne (and Becker) muscular dystrophy.
It leaves out Menkes disease, X-linked SCID, CYBB-related CGD, color blindness and androgen insensitivity, and three of its members (OTC deficiency, Fabry disease, G6PD deficiency) often affect heterozygous women.
Duchenne and its look-alikes
The classic Q-bank stem: a 3-year-old boy who climbs up his thighs to stand (Gowers sign), with enlarged calves, a markedly raised CK and a maternal uncle who died young of progressive weakness. That is Duchenne muscular dystrophy; discard the usual distractors like this:
| Option | Inheritance | What sets it apart |
|---|---|---|
| Duchenne | XLR (DMD) | Early childhood onset, Gowers sign, calf pseudohypertrophy, very high CK, absent dystrophin, dilated cardiomyopathy |
| Becker | XLR (DMD) | Later onset and milder; dystrophin reduced or abnormal, not absent |
| Emery-Dreifuss | XLR (EMD, FHL1) or autosomal (LMNA) | Early contractures of elbows, ankles and neck; upper-arm and lower-leg weakness; conduction defects and arrhythmias |
| Spinal muscular atrophy | AR (SMN1) | Motor neuron loss: hypotonia and proximal weakness, often from infancy; not a muscle-membrane disease |
| Myotonic dystrophy type 1 | AD (DMPK CTG repeat, anticipation) | Myotonia, distal weakness, cataracts, conduction defects; congenital form when inherited from the mother |
Practice question
A 30-year-old man has had bowed legs and short stature since childhood and has had several dental abscesses. Serum phosphate is low with inappropriately high urinary phosphate loss, and genetic testing finds a pathogenic PHEX variant. His wife is unaffected and has no family history of the condition. Which statement best describes the risk to their future children?
- A. Each child, son or daughter, has a 50% risk of being affected
- B. All sons will be affected and no daughters
- C. All daughters will be affected and no sons
- D. All daughters will be unaffected carriers and no children will be affected
- E. All children will be affected
Answer: C. X-linked hypophosphatemia is the classic X-linked dominant disorder. (MedlinePlus now labels it simply X-linked, but states the same rule: fathers pass the variant to all of their daughters and none of their sons, and females with one variant have signs similar to those in males.) The father gives his only X to every daughter and his Y to every son, so every daughter inherits the variant and, because one copy is enough, is affected; no son inherits it.
- A: the pattern for an affected heterozygous mother with an X-linked dominant disorder, or for an autosomal dominant disorder from either parent.
- B: reverses the logic. Only Y-linked traits pass from a father to all of his sons.
- D: the X-linked recessive pattern: daughters of an affected man are obligate carriers who are usually unaffected. With a dominant disorder, carrying the variant means being affected.
- E: with an X-linked dominant trait, every child is affected only when the mother is homozygous; mitochondrial disorders come only from mothers, never fathers.
Key takeaways
- No male-to-male transmission is the first clue to X-linked inheritance.
- XLR: mostly males, through carrier mothers; an affected father's daughters are all obligate carriers; a carrier mother's sons each have a 50% risk.
- XLD: an affected father → all daughters, no sons; an affected mother → half of her children; more affected females than males.
- Lyonization is random but can be skewed, producing manifesting carriers (Duchenne, Fabry, G6PD and OTC deficiency).
- XLD examples: X-linked hypophosphatemia, fragile X, Rett syndrome, incontinentia pigmenti, X-linked Alport syndrome (MedlinePlus labels the first and last simply X-linked).
- XLR list: the "Oblivious Female..." mnemonic, plus Menkes, X-linked SCID, X-linked CGD, color blindness and androgen insensitivity.
Sources
- Single-Gene Defects — Merck Manual Professional Edition (2025)
- What are the different ways a genetic condition can be inherited? — MedlinePlus Genetics (2021)
- Overview of Sex Chromosome Abnormalities — Merck Manual Professional Edition (2025)
- Duchenne and Becker muscular dystrophy — MedlinePlus Genetics (2016)
- Glucose-6-phosphate dehydrogenase deficiency — MedlinePlus Genetics (2023)
- Ornithine transcarbamylase deficiency — MedlinePlus Genetics (2017)
- Fragile X syndrome — MedlinePlus Genetics (2020)
- Rett syndrome — MedlinePlus Genetics (2018)
- Incontinentia pigmenti — MedlinePlus Genetics (2023)
- X-linked hypophosphatemia — MedlinePlus Genetics (2026)
- Alport syndrome — MedlinePlus Genetics (2023)
- Emery-Dreifuss muscular dystrophy — MedlinePlus Genetics (2017)
Frequently Asked Questions
How do you recognize an X-linked pedigree?
Look first for male-to-male transmission. A father passes his Y chromosome, not his X, to his sons, so father-to-son transmission rules out X-linked inheritance. Mostly affected males related through unaffected women, with skipped generations, suggests X-linked recessive inheritance. Both sexes affected in every generation, with an affected father passing the trait to all of his daughters and none of his sons, suggests X-linked dominant inheritance.
What is the difference between X-linked recessive and X-linked dominant inheritance?
In X-linked recessive inheritance, one variant copy causes disease in males, while heterozygous females are usually unaffected carriers. A carrier mother passes the condition to half of her sons and carrier status to half of her daughters, and all daughters of an affected man are carriers. In X-linked dominant inheritance, one copy causes disease in either sex: an affected father passes it to all daughters and no sons, and an affected mother to half of her children.
What are the most common X-linked recessive disorders?
High-yield X-linked recessive disorders include Duchenne and Becker muscular dystrophy, hemophilia A and B, G6PD deficiency, Bruton agammaglobulinemia, Wiskott-Aldrich syndrome, X-linked SCID, the X-linked form of chronic granulomatous disease, Fabry disease, Hunter syndrome, Lesch-Nyhan syndrome, OTC deficiency, Menkes disease, ocular albinism, red-green color blindness and androgen insensitivity syndrome. A popular memory aid is Oblivious Female Will Often Give Her Boys Her x-Linked Disorders. MedlinePlus now labels G6PD deficiency, Fabry disease and OTC deficiency simply X-linked, noting that many heterozygous women are affected.
What are examples of X-linked dominant disorders?
Classic X-linked dominant examples are X-linked hypophosphatemic rickets (PHEX), fragile X syndrome (FMR1 CGG repeat), Rett syndrome (MECP2), incontinentia pigmenti (IKBKG) and the X-linked form of Alport syndrome (COL4A5). Rett syndrome and incontinentia pigmenti occur mostly in females because affected males usually die early. Merck uses familial rickets and hereditary nephritis as its examples, and MedlinePlus classifies fragile X, Rett syndrome and incontinentia pigmenti as X-linked dominant but labels X-linked hypophosphatemia and X-linked Alport syndrome simply X-linked.
Can females have X-linked recessive disorders?
Yes. Early in development one X chromosome in each female cell is randomly inactivated, a process called lyonization. If inactivation is skewed toward silencing the normal X, a heterozygous woman can develop disease; MedlinePlus notes this for many women with G6PD or OTC deficiency, and Duchenne carriers can have weakness and cardiomyopathy. A female can also be affected if she has only one X chromosome, as in Turner syndrome, or inherits variants from an affected father and a carrier mother.
Is fragile X syndrome X-linked dominant or recessive?
MedlinePlus Genetics classifies fragile X syndrome as X-linked dominant, because one full mutation of the FMR1 gene can cause features in females as well as males, although males are usually more severely affected. The full mutation is a CGG repeat expansion above 200 that silences the gene. A mother's premutation of 55 to 200 repeats can expand to a full mutation in her eggs, whereas a father's premutation does not expand to a full mutation.