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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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MYH9-Related Disorders

, PhD and , MD.

Author Information
, PhD
Genetics Laboratory
Department of Reproductive and Developmental Science and Public Medicine Science
Institute for Maternal and Child Health - IRCCS Burlo Garofolo
University of Trieste
Trieste, Italy
, MD
Clinica Medica III
IRCCS Policlinico San Matteo
University of Pavia
Pavia, Italy

Initial Posting: ; Last Update: April 5, 2011.

Summary

Disease characteristics. MYH9-related disorders (MYH9RD) are characterized by large platelets (i.e., >20% of platelets >4 μm in diameter) and thrombocytopenia (platelet count <150x109/L), both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive high-frequency sensorineural hearing loss, presenile cataract, and renal disease manifesting initially as glomerulonephritis. Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all have MYH9 mutations and that their clinical picture often worsens throughout life as a result of late onset of non-hematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD.

Diagnosis/testing. In an individual with abnormally large platelets and platelet counts in the low to low-normal range, the next step in diagnosis of MYH9RD is an immunofluorescence test for detection of MYH9 protein aggregates in neutrophils. In those with a positive immunofluorescence test, molecular genetic testing of MYH9 is used to confirm the diagnosis. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD.

Management. Treatment of manifestations: For active hemorrhage, desmopressin (DDAVP) may shorten bleeding time in some individuals; otherwise, platelet transfusion is necessary. Hearing loss, renal complications, and cataract are managed in a standard fashion.

Prevention of primary manifestations: Platelet transfusion, desmopressin, or antifibrinolytic drugs can be used to reduce the risk of bleeding prior to surgery or invasive procedures.

Prevention of secondary complications: Regular dental care to prevent gingival bleeding.

Surveillance: In those with bleeding episodes, blood count at least every six months to identify anemia. In all affected individuals, annual urine analysis (including 2-hour protein) and measurement of serum concentration of creatinine prior to onset of renal disease; audiometric and ophthalmologic evaluations every three years prior to onset of hearing loss and cataract, respectively.

Agents/circumstances to avoid: Bleeding: drugs that inhibit platelet function or blood coagulation; activities with high risk for injury. Hearing loss: ototoxic drugs and hazardous noise. Glomerulonephritis: nephrotoxic agents. Cataract: glucocorticoids and radiation therapy.

Evaluation of relatives at risk: Screen at-risk newborns with molecular genetic testing if the family-specific mutation is identified; otherwise assess platelet count and size.

Genetic counseling. MYH9RD is inherited in an autosomal dominant manner. Approximately 35% of affected individuals represent simplex cases, half of whom have a documented de novo mutation. Each offspring of an individual with a MYH9RD has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

GeneReview Scope

MYH9-Related Disorders: Included Disorders
  • Epstein syndrome
  • Fechtner syndrome
  • May-Hegglin anomaly
  • Sebastian syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Clinical Diagnosis

MYH9-related disorders (MYH9RD) include Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, and Sebastian syndrome, thought to be separate disorders involving congenital macrothrombocytopenia prior to the understanding of their shared molecular genetic basis.

MYH9RD should be suspected in individuals with congenital macrothrombocytopenia characterized by the following:

  • Large platelets. Mean platelet diameter larger than 3.3 μm. Mean platelet diameter was 5.2 μm (range: 3.32-7.65 μm) in 15 persons with MYH9RD and 2.5 μm (range: 1.88-3.42 μm) in 40 healthy controls [Noris et al 2009].
  • Thrombocytopenia. Platelet count lower than 150x109/L (normal: 150 to 400x109/L)

    Note: Platelet count can be at the lower limit of normal range in some individuals with MYH9RD; platelets larger than normal are the only finding shared among all affected individuals.
  • Family history consistent with autosomal dominant inheritance

An association with or family history of one or more of the following later-onset clinical findings increases the likelihood of a MYH9RD:

  • High-frequency sensorineural hearing loss. See Deafness and Hereditary Hearing Loss Overview for discussion of audiologic methods to detect hearing loss.
  • Glomerulonephritis. Note: In MYH9RD, hematuria may result from thrombocytopenia rather than glomerular disease; therefore, proteinuria is a more reliable indicator of glomerular involvement than hematuria. Increased serum creatinine concentration indicates impaired glomerular filtration rate and risk for end-stage renal disease (ESRD).
  • Presenile cataract (occurring in early or middle life). Cataracts are detected on slit lamp evaluation.

Testing

Assessment of platelet size and number. Manual assessment of platelet number and size is necessary in MYH9RD. Electronic cell counters do not recognize the giant platelets of MYH9RD and therefore underestimate both platelet count and platelet volume.

Microscopy of peripheral blood smears suggests the diagnosis of a MYH9RD when Döhle-like bodies (faint, light blue basophilic inclusion bodies similar to the Döhle bodies that may be found in persons with an infection) are identified in the cytoplasm of neutrophils. Because microscopy requires an expert operator and has low sensitivity, immunochemistry or immunofluorescence analysis using an anti-myosin-9 antibody is preferable.

Immunofluorescence of peripheral blood smears is a highly sensitive way to determine the presence and distribution of MYH9 protein aggregates in neutrophils, which are present from birth [Kunishima et al 2003].

  • In controls, the MYH9 protein is uniformly distributed.
  • In individuals with MYH9RD, myosin-9 (MYH9 protein) aggregates in inclusions that vary in number, size, and shape.
    Note: (1) Immunofluorescent-positive MYH9 protein aggregates have been present in all individuals with a MYH9 mutation reported to date. (2) No MYH9 mutations have been detected in 36 individuals with a clinical picture similar to that of MYH9RD but without immunofluorescent-positive MYH9 protein aggregates [Savoia et al 2010].

Molecular Genetic Testing

Gene. MYH9 is the only gene in which mutations are known to cause the MYH9RDs.

Clinical testing

  • Sequence analysis/mutation scanning of the coding exons of MYH9 may be performed with a tiered approach that focuses initially on exons in which mutations are most commonly found, then on exons in which mutations have previously been identified, and finally on the remainder of the gene.
  • Deletion/duplication analysis. Because a large deletion of 1220 nucleotides leading to an in-frame removal of exon 25 has been identified in MYH9 [Kunishima et al 2008b], deletion/duplication analysis may be appropriate in families with a strong clinical history and no identifiable MYH9 mutation.

Table 1. Summary of Molecular Genetic Testing Used in MYH9-Related Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3, 4
MYH9Sequence analysis 5Sequence variants98% 6
Deletion/duplication analysis 7(Multi)exonic and whole-gene deletionsUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Based on data from the Italian Registry of MYH9-Related Disease

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Affected individuals: those with an aggregate distribution of MYH9 protein in neutrophils [Savoia et al 2010]

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • In an individual with abnormally large platelets and platelet counts in the low to low-normal range, perform immunofluorescence test to detect MYH9 protein aggregates in neutrophils. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD.
  • In those with a positive immunofluorescence test, carry out molecular genetic testing of MYH9 to identify a disease-causing mutation. Tiered approaches to sequence analysis and exon numbering may vary among laboratories (see Molecular Genetics for exon numbering information).

    One tiered approach:
    • Tier 1. Of the 40 coding exons of MYH9, sequence first the five exons in which mutations are found in 84% of cases. Missense mutations at amino acid residues 96 (exon 1), 702 (exon 17), 1165 (exon 27), 1424 (exon 31), and 1841 (exon 39), or nonsense and frameshift mutations in exon 41 have been found in 79% of affected individuals (see Table 2).
    • Tier 2. When mutations are not detected in Tier 1 testing, the analysis is extended to exons 2, 11, 25, 26, 32, 33, 35 and 38, in which the remaining 16% of mutations have been identified [Pecci et al 2008b].
    • Tier 3. In individuals without an identifiable mutation in Tier 1 or Tier 2 testing, sequence analysis of all coding exons is performed.
    • Tier 4. Deletion/duplication analysis may be appropriate in families with a strong clinical history and no identifiable MYH9 mutation by sequence analysis. A large deletion of 1220 nucleotides leading to an in-frame removal of exon 25 has been identified in MYH9 [Kunishima et al 2008b]; such mutations cannot be detected by sequence analysis of genomic DNA.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prognostication. Molecular genetic testing is performed to detect the family-specific MYH9 mutation to be used for genotype/phenotype correlation, which can help assess the risk of developing the variable findings of hearing impairment, glomerulonephritis, and cataract.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

In all individuals with a MYH9-related disorder (MYH9RD), macrothrombocytopenia is present at birth [Pecci et al 2008b]. Thrombocytopenia ranges from mild to severe and remains stable in an individual throughout life. Individuals with low platelet counts usually have easy bruising, petechiae, and bleeding from the gums and nose. Affected females may have menorrhagia. Life-threatening bleeding is rare.

The other three manifestations of MYH9RD, high-frequency sensorineural hearing loss, glomerulonephritis, and cataract, can develop anytime between infancy and adulthood; the overall annual rates per 100 affected persons are 2.08, 0.84, and 0.48, respectively [Pecci et al 2008b] (i.e., for example, 0.48% of individuals with MYH9RD develop cataract every year).

Onset of hearing loss is distributed evenly from the first to sixth decade. Of those who develop hearing loss, 33% do so before age 20 years, 31% between ages 20 and 40 years, and 36% after age 40 years. Once diagnosed, hearing loss progresses over time. Hearing loss interfering with activities of daily living affects more than 90% of those individuals who have an abnormal audiometric examination [Pecci et al 2008b].

Glomerulonephritis presents with proteinuria and microhematuria. The mean age at onset is 23 years. Of those who develop renal disease, 77% are diagnosed before age 30 years. In most cases, renal disease evolves to ESRD in a few years [Pecci et al 2008b].

The mean age of onset of cataract is 23 years [Pecci et al 2008b]. Cataracts progress over time.

Genotype-Phenotype Correlations

Most individuals with mutations that involve the motor domain of the MYH9 protein have severe thrombocytopenia and a high risk of developing glomerulonephritis and deafness.

Individuals with mutations that involve the tail domain have significantly higher platelet counts and a lower risk of glomerulonephritis and hearing loss than individuals with a mutation that involves the motor domain.

  • Mutations in the arginine residue at amino acid 702 of the motor domain are associated with the most severe phenotype: severe thrombocytopenia (platelet count usually <40x109/L), glomerulonephritis, and hearing loss before age 40 years.
  • The p.Arg1933Ter mutation of the tail domain is never associated with glomerulonephritis. No individual with this mutation has developed deafness before age 60 years.
  • Mutations at residues Asp1424 or Glu1841 of the tail domain are associated with an intermediate risk of developing glomerulonephritis and hearing loss. Therefore, affected individuals can have both severe and mild phenotypes.

The risk of cataract in MYH9RD is low except among individuals with mutations at residue Asp1424 in the tail domain; of this group, 1.61 persons out of 100 develop cataracts each year.

Penetrance

Penetrance is complete for the following congenital findings:

  • Large platelets
  • MYH9 aggregates in neutrophils

Except for a few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150x109/L), thrombocytopenia is a congenital manifestation of the disease.

Expressivity varies for onset and severity of sensorineural deafness, glomerulonephritis, and presenile cataract.

Nomenclature

In the past, the conditions included in MYH9RD were known as

  • Epstein syndrome
  • Fechtner syndrome
  • May-Hegglin anomaly
  • Sebastian syndrome (Sebastian platelet syndrome)

These four disorders, characterized by thrombocytopenia with giant platelets, were classified on the basis of morphologic aspects of Döhle-like bodies and different combinations of the three other manifestations of MYH9RD: hearing loss, glomerulonephritis, and cataract. However, because the phenotype of a person with a MYH9 mutation often evolves over time, the diagnosis of an individual can change over time based on the appearance of a new finding or findings. Moreover, members of the same family may have different phenotypes and receive different diagnoses within the spectrum of MYH9RD. For these reasons, MYH9RD has been proposed as a new nosologic entity that includes all individuals with MYH9 mutations independent of their neutrophil phenotype (i.e., presence of morphologic aspects of Döhle-like bodies) and clinical phenotype (late-onset non-hematologic manifestations).

Prevalence

MYH9RD is considered a very rare disease. The Italian Registry for MYH9RD includes 152 affected individuals, indicating that the prevalence of the disorder in Italy is at least 2.5 in 1,000,000. Because mild forms are discovered incidentally and severe forms are often misdiagnosed as other disorders, the actual prevalence is expected to be higher.

MYH9RD has been diagnosed worldwide and there is no evidence of variation in prevalence across ethnic populations.

Differential Diagnosis

MYH9-related disorder (MYH9RD) should be suspected in all individuals with congenital thrombocytopenia and giant platelets. It should also be considered when macrothrombocytopenia is discovered incidentally in infancy or adulthood and no previous blood counts are available to determine if the macrothrombocytopenia is congenital or acquired.

Absence of thrombocytopenia in other family members does not exclude MYH9RD because the frequency of de novo mutation is high.

The differential diagnosis of MYH9RD should take into consideration acquired and congenital forms of thrombocytopenia as well as collagen IV-related nephropathies.

Acquired thrombocytopenia. Differentiating MYH9RD from acquired forms of thrombocytopenia may be difficult and several individuals with MYH9RD have been misdiagnosed with idiopathic (autoimmune) thrombocytopenic purpura (ITP) and treated accordingly. A simple and adequate way to differentiate MYH9RD as well as the other inherited macrothrombocytopenias from acquired forms of thrombocytopenia is a peripheral blood film evaluation because a mean platelet diameter larger than 3.3 μm distinguishes ITP from genetic forms with a sensitivity of 0.89 and a specificity of 0.88 [Noris et al 2009].

The immunofluorescence test to detect MYH9 protein aggregates can also be used to distinguish MYH9RD from ITP [Yoshinari et al 2004].

Congenital thrombocytopenia. The following inherited thrombocytopenias presenting with large platelets should be considered in the differential diagnosis of MYH9RD:

  • Bernard-Soulier syndrome, an autosomal recessive nonsyndromic thrombocytopenia resulting from mutations in the genes coding for platelet glycoproteins (GP) GPIbα, GPIbβ, and GPIX, which together with subunit GPV constitute the von Willebrand factor receptor, GPIb/IX/V. The quantitative or qualitative abnormalities of the complex can be identified by flow cytometry or biochemical methods, as well as by failure of platelets to agglutinate in vitro after ristocetin stimulation. Approximately 130 cases with a molecular diagnosis have been reported in the literature.
  • Gray platelet syndrome, a very rare, nonsyndromic thrombocytopenia with uncertain transmission pattern and unknown etiology. The distinguishing feature is appearance of “pale” platelets on peripheral blood films as a result of lack of alpha-granules. Electron microscopy or immunofluorescence analysis of platelets can reveal this defect. Approximately 20 families have been reported in the literature.
  • X-linked thrombocytopenia with GATA1 mutation, another rare condition characterized by a mild to moderate hemolytic anemia sometimes associated with hemoglobin changes similar to heterozygous beta-thalassemia. An estimated six families have been reported in the literature.

Collagen IV-related nephropathies, including X-linked and autosomal (dominant and recessive) forms of Alport syndrome and thin basement membrane nephropathy. Whereas the latter is characterized mainly by persistent microscopic hematuria, which rarely progresses to renal failure, Alport syndrome is associated with renal disease that evolves from microscopic hematuria to proteinuria, progressive renal insufficiency, and ESRD. It is also characterized by extrarenal abnormalities including progressive sensorineural hearing loss (usually present by late childhood or early adolescence), anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. Platelet defects have not been described in either Alport syndrome or thin basement membrane nephropathy. Therefore, whenever nephropathies are associated with macrothrombocytopenia, MYH9RD should be strongly considered.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a MYH9-related disorder (MYH9RD), the following evaluations are recommended:

  • In individuals with bleeding episodes, blood count to evaluate for anemia
  • In individuals with anemia, serum concentration of iron, folic acid, and vitamin B12
  • Audiometric evaluation
  • Urine analysis (including 24-hour protein) and measurement of serum concentration of creatinine
  • In individuals with established renal involvement, testing appropriate to the severity of renal disease
  • Ophthalmologic examination

Treatment of Manifestations

Bleeding tendency. Transfusions of platelet concentrates are currently used to transiently increase platelet count. However, platelet transfusions have associated risks of possible alloimmunization, subsequent refractoriness to platelet infusions, infectious diseases, and febrile reactions. Thus, platelet transfusions should only be used as treatment for an active hemorrhage that cannot be otherwise managed and as prophylaxis prior to surgery or other major hemostatic stresses. When available, platelets from HLA-matched donors should be used to prevent or overcome alloimmunization.

A phase II study in 12 persons with MYH9RD and severe thrombocytopenia revealed that eltrombopag, an oral drug mimicking the natural hormone that stimulates platelet production, greatly increased platelet counts and abolished bleeding tendency in most cases [Pecci et al 2010]. At the present time, this drug is approved in the US and Europe only for patients with some forms of acquired thrombocytopenia.

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) has been reported to shorten bleeding time in some individuals with MYH9RD [Balduini et al 1999]. As not all affected individuals respond to the treatment, a test dose is recommended to identify those who will benefit from this treatment either in future bleeding episodes or in prevention of bleeding at the time of invasive procedures.

Deafness. In four profoundly deaf individuals, hearing was greatly improved by cochlear implant [Balduini, unpublished data].

Glomerulonephritis. Four affected individuals with renal involvement had their proteinuria greatly reduced by treatment with angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors [Pecci et al 2008a]. It is premature to conclude whether this therapeutic approach prevents or delays the development of ESRD.

Dialysis or kidney transplantation is required in individuals with ESRD.

Cataracts. Cataract surgery remedies clouding of the lens.

Prevention of Primary Manifestations

Bleeding tendency. Thrombocytopenia cannot be prevented.

The risk of bleeding can be significantly reduced by patient education regarding drugs that affect platelet function.

Affected individuals should be prepared for surgery and invasive procedures with platelet transfusions, desmopressin, or antifibrinolytic drugs, according to the individual's platelet count and bleeding tendency.

Whereas oral contraceptives may be used to prevent menorrhagia, they increase the risk of thrombosis, which has also been described in MYH9RD. Thus, the balance between risks and benefits associated with use of oral contraceptives should be carefully considered [Heller et al 2006, Nishiyama et al 2008].

Prevention of Secondary Complications

Regular dental care and good oral hygiene are essential to prevent gingival bleeding.

Surveillance

In individuals with bleeding episodes, blood count should be performed every six months (or more frequently in case of recurrent profuse bleeding) to identify anemia.

Audiometric evaluations should be performed every three years to determine the onset of hearing loss. Once hearing loss is identified, frequency of screening is determined by the treating hearing specialists.

Urine analysis (including 24-hour protein) and measurement of serum concentration of creatinine are required each year. In individuals with an established renal defect, type and frequency of the tests depend on the clinical severity.

Ophthalmologic evaluations should be performed every three years to determine the onset of cataract. Once cataract is identified, frequency of evaluations is determined by the treating ophthalmologist.

Agents/Circumstances to Avoid

Bleeding tendency

  • Agents. Drugs that inhibit platelet function or blood coagulation:
    • Nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, which are strong inhibitors of platelet aggregation
    • Other substances that interfere with platelet function include some antibiotics, cardiovascular, psychotropic, and oncologic drugs, drugs that affect platelet cAMP, anesthetics, volume expanders, antihistamines, and radiographic contrast agents

      Note: Physicians should try to avoid prescribing drugs that increase the risk of bleeding in individuals with MYH9RD.
  • Circumstances. Risk of trauma.

Hearing loss

  • Agents. Ototoxic drugs (e.g., aminoglycoside antibiotics, salicylates in large quantities, loop diuretics, some drugs used in chemotherapy regimens) unless strictly required
  • Circumstances. Exposure to hazardous noise. If noise exposure cannot be avoided, use ear devices (e.g., earplugs, headphones) to attenuate intense sound.

Glomerulonephritis

  • Agents. Agents that can damage renal function, including radiocontrast, antibiotics, NSAIDs, diuretics, and oncologic drugs. The balance between benefit and risk of such agents should be considered, especially in individuals with established kidney involvement or with MYH9 mutations known to predispose to kidney failure.

Cataract

  • Agents. Glucocorticoids and radiation therapy, which predispose to development of cataracts

Evaluation of Relatives at Risk

Assessing platelet count and size in a newborn at risk for MYH9RD identifies those at risk for bleeding.

If the family-specific mutation is known, molecular genetic testing can be used to evaluate at-risk family members so that early diagnosis can inform treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

As for other forms of thrombocytopenia, a platelet count above 80×109/L is recommended for delivery, particularly when an epidural or spinal anesthetic is planned.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MYH9-related disorders (MYH9RD) are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 65% of individuals diagnosed with MYH9RD have an affected parent.
  • A proband with MYH9RD may have the disorder as the result of a new mutation. Thirty-five percent of affected individuals represent simplex cases (i.e., a single occurrence in a family); half of whom are ascertained as having a de novo mutation [Kunishima et al 2005, Pecci et al 2008b].
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. One person with germline mosaicism has been reported [Kunishima et al 2009].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing if the family-specific mutation is known. Alternatively, when the family-specific mutation is not known or a mild phenotype resulting from potential somatic mosaicism is suspected in one parent, hematologic testing (e.g., evaluation of platelet number and size, distribution of the MYH9 protein in neutrophils) should be proposed. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by healthcare professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until molecular genetic testing and/or appropriate hematologic testing has been performed.

Note: (1) Sixty-five percent of individuals diagnosed with MYH9RD have an affected parent; the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected. In one family, the father of a proband with a typical MYH9RD had a mild phenotype associated with somatic mosaicism [Kunishima et al 2005].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the mutation and being affected.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Medline Plus
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261
    Email: info@kidney.org
  • Platelet Disorder Support Association (PDSA)
    133 Rollins Avenue
    #5
    Rockville MD 20852
    Phone: 877-528-3538 (toll-free); 301-770-6636
    Fax: 301-770-6638
    Email: pdsa@pdsa.org
  • Italian Registry of MYH9-Related Disease
    Clinica Medica III IRCCS Policlinico
    San Matteo Piazzale Golgi, 2
    Pavia 27100
    Italy
    Phone: +39 0382.526284; +39 0382 501385
    Fax: +39 0382 526223
    Email: c.balduini@smatteo.pv.it; alessandro.pecci@unipv.it

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MYH9-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for MYH9-Related Disorders (View All in OMIM)

153640FECHTNER SYNDROME; FTNS
153650EPSTEIN SYNDROME
155100MAY-HEGGLIN ANOMALY; MHA
160775MYOSIN, HEAVY CHAIN 9, NONMUSCLE; MYH9
605249SEBASTIAN SYNDROME; SBS

Gene structure. MYH9 consists of 41 exons. The first exon does not code for amino acids. The first methionine of the open reading frame is in exon 2. Exon numbering may vary among different testing laboratories. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Two non-pathogenic allelic variants in MYH9 are listed in Table 2.

Pathogenic allelic variants. See Table 2. Most pathogenic variants are missense mutations; a few are nonsense mutations or small in-frame deletions affecting either motor or coiled-coil domains. Some mutations are nonsense or frameshift alterations that are all located in the last coding exon. Only 25 of the total 1960 amino acid residues in myosin-9 (MYH9 protein) are altered by 33 reported disease-causing nucleotide changes.

Table 2. Selected MYH9 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Benignc.2900T>Ap.Val967GluNM_002473​.4
NP_002464​.1
c.4876A>Gp.Ile1626Val
Pathogenicc.287C>Tp.Ser96Leu
c.2104C>Tp.Arg702Cys
c.2105G>Ap.Arg702His
c.2114G>A 1p.Arg705His 1
c.3493C>Tp.Arg1165Cys
c.3494G>Tp.Arg1165Leu
c.4270G>Cp.Asp1424His
c.4270G>Ap.Asp1424Asn
c.4270G>Tp.Asp1424Tyr
c.5521G>Ap.Glu1841Lys
c.5797C>Tp.Arg1933Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Associated with DFNA17 (see Genetically Related Disorders)

Normal gene product. The 1960 amino-acid product of MYH9 is non-muscle myosin heavy chain A of myosin superfamily class II (myosin-9) (also called MYH9 protein). MYH9 protein is expressed in most cells and tissues, where it is involved in several functions including cytokinesis, cell motility, and maintenance of cell shape [Sellers 2000]. MYH9 protein, as all myosins of class II, is a hexameric enzyme composed of two heavy chains and two pairs of light chains. Dimerization of the heavy chains yields a polar structure. The N-terminal halves form two globular heads (motor domain) that bind the light chains, interact with actin, and hydrolyze ATP, whereas the C-terminal halves form a coiled-coil alpha helix (tail domain), which allows the molecules to polymerize into bipolar filaments in both muscle and non-muscle cells.

Abnormal gene product. Recent reports suggest that MYH9 pathogenic allelic variants act through different mechanisms in different cell types and that cell-specific regulation mechanisms function in MYH9RD [Pecci et al 2005, Kunishima et al 2008a]. In neutrophils the defective gene product aggregates and forms inclusion bodies that also contain the wild-type protein [Kunishima et al 2008a]. In platelets and megakaryocytes the mutant polypeptide is also expressed but at lower levels, and it does not form inclusions [Deutsch et al 2003, Kunishima et al 2008a]. Little is known about the expression of the defective protein in kidney, lens, and inner ear. Because MYH9RD is an autosomal dominant disorder and myosin consists of dimerization of two MYH9 protein molecules, the pathogenic mechanisms are likely to be associated with a dominant-negative effect of the mutations. This hypothesis was also supported by in vitro experiments showing that mutant MYH9 proteins, expressed from any of four known pathogenic alleles, interfered with the proper assembly of wild-type myosin filaments [Franke et al 2005]. However, the mechanisms leading to MYH9RD are poorly defined at both the molecular and cellular level.

In mouse megakaryocytes, phosphorylation of the myosin light chain has an important role in regulating proplatelet formation and platelet release [Chen et al 2007]. Myosin-9 (MYH9 protein) is a negative regulator of thrombopoiesis mediated by the Rho-ROCH pathway. It has been hypothesized that when the MYH9 protein is defective, platelet release occurs prematurely in the marrow interstitium instead of the sinusoidal vasculature, thus leading to thrombocytopenia.

References

Literature Cited

  1. Balduini CL, Noris P, Belletti S, Spedini P, Gamba G. In vitro and in vivo effects of desmopressin on platelet function. Haematologica. 1999;84:891–6. [PubMed: 10509036]
  2. Chen Z, Naveiras O, Balduini A, Mammoto A, Conti MA, Adelstein RS, Ingber D, Daley GQ, Shivdasani RA. The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood. 2007;110:171–9. [PMC free article: PMC1896110] [PubMed: 17392504]
  3. Deutsch S, Rideau A, Bochaton-Piallat ML, Merla G, Geinoz A, Gabbiani G, Schwede T, Matthes T, Antonarakis SE, Beris P. Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. Blood. 2003;102:529–34. [PubMed: 12649151]
  4. Franke JD, Dong F, Rickoll WL, Kelley MJ, Kiehart DP. Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. Blood. 2005;105:161–9. [PubMed: 15339844]
  5. Heller PG, Pecci A, Glembotsky AC, Savoia A, Negro FD, Balduini CL, Molinas FC. Unexplained recurrent venous thrombosis in a patient with MYH9-related disease. Platelets. 2006;17:274–5. [PubMed: 16769605]
  6. Hildebrand MS, de Silva M, McKinlay Gardner RJ, Rose E, De Graaf CA, Bahlo M, Dahl HHM. Cochlear Implants for DFNA17 deafness. Laryngoscope. 2006;116:2211–15. [PubMed: 17146397]
  7. Kunishima S, Hamaguchi M, Saito H. Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood. 2008a;111:3015–23. [PubMed: 18192507]
  8. Kunishima S, Matsushita T, Hamaguchi M, Saito H. Identification and characterization of the first large deletion of the MYH9 gene associated with MYH9 disorders. Eur J Haematol. 2008b;80:540–4. [PubMed: 18284620]
  9. Kunishima S, Matsushita T, Kojima T, Sako M, Kimura F, Jo EK, Inoue C, Kamiya T, Saito H. Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A (NMMHCA) in MYH9 disorders: association of subcellular localization with MYH9 mutations. Lab Invest. 2003;83:115–22. [PubMed: 12533692]
  10. Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M, Saito H. First description of somatic mosaicism in MYH9 disorders. Br J Haematol. 2005;128:360–5. [PubMed: 15667538]
  11. Kunishima S, Takaki K, Ito Y, Saito H. Germinal mosaicism in MYH9 disorders: a family with two affected siblings of normal parents. Br J Haematol. 2009;145:260–2. [PubMed: 19208103]
  12. Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am J Hum Genet. 2000;67:1121–8. [PMC free article: PMC1288554] [PubMed: 11023810]
  13. Nishiyama Y, Akaishi J, Katsumata T, Katsura K, Katayama Y. Cerebral infarction in a patient with macrothrombocytopenia with leukocyte inclusions (MTCP, May-Hegglin anomaly/Sebastian syndrome). J Nippon Med Sch. 2008;75:228–32. [PubMed: 18781047]
  14. Noris P, Klersy C, Zecca M, Arcaini L, Pecci A, Melazzini F, Terulla V, Bozzi V, Ambaglio C, Passamonti F, Locatelli F, Balduini CL. Platelet size distinguishes between inherited macrothrombocytopenias and immune thrombocytopenia. J Thromb Haemost. 2009;7:2131–6. [PubMed: 19740094]
  15. Pecci A, Canobbio I, Balduini A, Stefanini L, Cisterna B, Marseglia C, Noris P, Savoia A, Balduini CL, Torti M. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet. 2005;14:3169–78. [PubMed: 16162639]
  16. Pecci A, Granata A, Fiore CE, Balduini CL. Renin-angiotensin system blockade is effective in reducing proteinuria of individuals with progressive nephropathy caused by MYH9 mutations (Fechtner-Epstein syndrome). Nephrol Dial Transplant. 2008a;23:2690–2. [PubMed: 18503011]
  17. Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat. 2008b;29:409–17. [PubMed: 18059020]
  18. Pecci A, Gresele P, Klersy C, Savoia A, Noris P, Fierro T, Bozzi V, Mezzasoma AM, Melazzini F, Balduini CL. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood. 2010;116:5832–7. [PubMed: 20844233]
  19. Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, Mumford A, Heller PG, Noris P, De Groot MR, Giani M, Freddi P, Scognamiglio F, Riondino S, Pujol-Moix N, Fabris F, Seri M, Balduini CL, Pecci A. Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Thromb Haemost. 2010;103:826–32. [PubMed: 20174760]
  20. Sellers JR. Myosins: a diverse superfamily. Biochim Biophys Acta. 2000;1496:3–22. [PubMed: 10722873]
  21. Yoshinari M, Kunishima S, Miyabayashi S, Saito H, Tsuchiya S. A unique immunofluorescence method promotes accurate diagnosis in MYH9 disorders: a case report. J Pediatr Hematol Oncol. 2004;26:579–83. [PubMed: 15342975]

Chapter Notes

Revision History

  • 5 April 2011 (me) Comprehensive update posted live
  • 25 June 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 20 November 2008 (me) Review posted live
  • 9 July 2008 (as) Original submission
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