MYH9-Related Disease

Clinical characteristics.

MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis (i.e., >40% of platelets larger than 3.9 μm in diameter), thrombocytopenia (platelet count <150 x 10⁹/L), and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes. Most affected individuals develop one or more additional extrahematologic manifestations of the disease over their lifetime, including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes.

Diagnosis/testing.

The diagnosis of MYH9-related disease is established in a proband with suggestive findings and a heterozygous pathogenic variant in MYH9 identified by molecular genetic testing.

Management.

Treatment of manifestations: For most active hemorrhages, consider local measures as the first-line treatment; transfusion of platelet concentrates should be used for active hemorrhages that cannot be otherwise managed, life- or organ-threatening hemorrhages, and/or bleeding at critical sites. Whenever necessary, eltrombopag or platelet transfusion should be used to prepare affected individuals for elective surgery. Antifibrinolytic agents and desmopressin are also used for covering hemostatic challenges or treating hemorrhages. Hearing loss, renal complications, and cataracts are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation.

Surveillance: For individuals with moderate or severe thrombocytopenia: at least annual (and in case of bleeding and/or changes in bleeding diathesis) microscopic assessment of platelet count and blood count to screen for anemia. Screening for individuals not currently under treatment for the following: annually (or every 6 months in individuals with high-risk MYH9 genotypes) for nephropathy, and every three years for hearing loss, cataracts, and abnormal liver enzymes.

Agents/circumstances to avoid: Drugs that inhibit platelet function or reduce platelet count, and drugs that are ototoxic, nephrotoxic, or hepatotoxic should be used only after assessment of risk-to-benefit ratio. Hazardous noise and activities with high risk of injury should be avoided.

Evaluation of relatives at risk: Clarify the status of all first-degree relatives of an affected individual in order to establish appropriate management (including treatment and surveillance) and awareness of agents and circumstances to avoid.

Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; in general, a platelet count of ≥50 x 10⁹/L is recommended for delivery.

Genetic counseling.

MYH9-RD is inherited in an autosomal dominant manner. Approximately 35% of probands represent simplex cases, most of whom have a documented de novo pathogenic variant. Each child of an individual with MYH9-RD has a 50% chance of inheriting the MYH9 pathogenic variant. Once the MYH9 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

MYH9-RD should be suspected in individuals with the following clinical and laboratory findings and family history.

Clinical findings

• Manifestations of thrombocytopenia
  • Easy bruising
  • Spontaneous mucocutaneous bleeding
  • Excessive bleeding after hemostatic challenges (major or minor surgery, deliveries, treatment with antiplatelet drugs)
• Sensorineural hearing loss ranging from a slight defect occurring in the elderly to profound deafness that may manifest at a young age
• Glomerular nephropathy manifest as proteinuria, with possible evidence of chronic kidney disease
• Presenile cataract (occurring in early or middle life)

Laboratory findings

• Platelet abnormalities
  • Thrombocytopenia. Platelet count <150 x 10⁹/L (normal: 150-400 x 10⁹/L)
  • Platelet macrocytosis. Extreme platelet macrocytosis present from birth, a hallmark of MYH9-RD, is a crucial suggestive finding. Mean platelet diameter was 4.5 μm (95% confidence interval, 4.2-4.8) in 125 persons with MYH9-RD compared to 2.6 μm (95% confidence interval, 2.4-2.7) in 55 healthy controls [Noris et al 2014a].
    Giant platelets (i.e., platelets larger than red blood cells) are invariably present on examination of blood smears of persons with MYH9-RD.
    Moreover, a mean platelet diameter >3.7 μm and/or the finding that >40% of platelets are larger than 3.9 µm (i.e., about half the diameter of a red blood cell) has very good sensitivity and specificity in distinguishing MYH9-RD from the other forms of inherited or acquired thrombocytopenia (see Differential Diagnosis) [Noris et al 2014a].
    Note: Electronic cell counters do not recognize the largest platelets of individuals with MYH9-RD, and therefore underestimate both platelet count and size.
• Neutrophil abnormalities
  • Döhle-like bodies. Faint, slightly basophilic inclusion bodies in the cytoplasm of neutrophils (similar to the Döhle bodies that may be found in persons with an infection) are observed on microscopic assessment of a peripheral blood smear after conventional staining (e.g., May-Grünwald-Giemsa).
    Note: Döhle-like bodies, present in 42%-84% of individuals with MYH9-RD, may escape detection because they can be very faint and/or small [Kunishima et al 2003, Seri et al 2003, Pecci et al 2018].
  • Typical aggregates of the MYH9 protein in the cytoplasm of neutrophils observed on immunofluorescence staining of a peripheral blood smear:
    • Are present at birth and throughout the life span;
    • Can be detected in all individuals with MYH9-RD. For this reason, assay of immunofluorescence staining of MYH9 protein distribution in neutrophils has been validated as a diagnostic test for MYH9-RD with close to 100% specificity and sensitivity [Kunishima et al 2003, Savoia et al 2010, Kitamura et al 2013, Greinacher et al 2017].
      Note: in neutrophils of unaffected individuals, MYH9 protein is uniformly distributed.
• Elevated liver enzymes (serum alanine aminotransferase and/or aspartate aminotransferase and occasionally serum gamma-glutamyltransferase)

Family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) or the affected individual may represent a simplex case (i.e., a single occurrence in a family). Therefore, absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MYH9-related disease is established in a proband with suggestive findings and a heterozygous pathogenic variant in MYH9 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous MYH9 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. In these cases, the search for typical aggregates of the MYH9 protein in neutrophils on immunofluorescence staining of blood smears may be a useful tool to assess the pathogenicity of the variant [Greinacher et al 2017].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MYH9-related disease has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in MYH9-Related Disease

Clinical Description

MYH9-related disease (MYH9-RD) is characterized in all affected individuals by hematologic features present from birth consisting of platelet macrocytosis (i.e., >40% of platelets >3.9 μm in diameter), thrombocytopenia (platelet count <150 x 10⁹/L), and aggregates of the MYH9 protein in the cytoplasm of neutrophil granulocytes. Most affected individuals develop one or more additional extrahematologic manifestations of the disease over their lifetime, including sensorineural hearing loss, renal disease (manifesting initially as glomerular nephropathy), presenile cataracts, and/or elevation of liver enzymes [Pecci et al 2014a, Pecci et al 2018].

Table 2.

MYH9-Related Disease: Frequency of Select Features

Platelet macrocytosis is present from birth in all individuals with MYH9-RD (see Diagnosis, Suggestive Findings).

Thrombocytopenia ranges from mild to severe. The degree of thrombocytopenia usually remains stable in each individual throughout life. Because platelet counts at the lower limit of the normal range have been reported in very few individuals with MYH9-RD, platelet macrocytosis and aggregates of the MYH9 protein in neutrophils are the only findings shared among all affected individuals.

Presence and severity of a spontaneous bleeding tendency correlate with the degree of thrombocytopenia. Most affected individuals have no spontaneous bleeding or only easy bruising, and are at risk of significant hemorrhages only after hemostatic challenges. About 30% of persons with MYH9-RD have spontaneous mucocutaneous bleeding – mainly menorrhagia, epistaxis, and gum bleeding [Pecci et al 2014a]. Life-threatening bleeding is rare.

Sensorineural hearing loss is present in about 50% of individuals evaluated at a mean age of 33 years and is expected to occur in most individuals over time [Pecci et al 2014a]. The mean age at onset is 31 years. Onset of hearing loss is distributed evenly from the first to sixth decade. Of those who develop hearing loss, 36% do so before age 20 years, 33% between ages 20 and 40 years, and 31% after age 40 years.

Hearing loss is usually bilateral. Once diagnosed, hearing loss frequently progresses over time, although it can remain stable in a minority of affected individuals. Earlier-onset hearing loss often progresses more rapidly and may result in severe-to-profound deafness [Verver et al 2016].

Hearing loss interferes with activities of daily living in 90% of individuals who have an abnormal audiometric examination [Pecci et al 2014a].

Glomerular nephropathy presents with proteinuria and microhematuria. However, in MYH9-RD, hematuria may result from thrombocytopenia rather than glomerular disease; therefore, proteinuria is the more reliable indicator of glomerular involvement.

The mean age at onset is 27 years. Of those who develop renal disease, 72% are diagnosed before age 35 years. In most individuals with nephropathy, kidney damage is progressive and evolves to end-stage renal disease (ESRD). Among those with nephropathy, the overall annual rate for progression to ESRD is 6.79 per 100 affected persons. After a median follow up of 36 months, 64% of 61 individuals with nephropathy developed chronic kidney disease and 43% developed ESRD [Pecci et al 2014a]. In some cases, kidney damage may appear later in life and/or show a slower progression.

Cataracts. The mean age of onset of cataracts is 37 years, but congenital cataracts have been reported. In most individuals, cataracts are bilateral and progress over time.

Elevated liver enzyme levels. Elevated aspartate aminotransferase and/or alanine aminotransferase (possibly associated with increased gamma-glutamyltransferase) usually remains stable over time. In some affected individuals, normalization of enzyme levels has been observed. Progression to impairment of liver function has not been reported in any affected individual [Pecci et al 2012, Favier et al 2013].

Genotype-Phenotype Correlations

Observed genotype-phenotype correlations are discussed in this section. (See Molecular Genetics, Table 8 for more details.)

Individuals with pathogenic variants involving the head domain of the MYH9 protein have more severe thrombocytopenia compared to those with pathogenic variants affecting the tail domain.

The risk of developing kidney damage, hearing loss, and cataract also depends on the specific MYH9 pathogenic variant [Pecci et al 2014a].

• Pathogenic variants in the codon for arginine residue 702 (located in the short functional SH1 helix of the head domain) are associated with the most severe phenotype. Individuals with Arg702 substitutions present with severe thrombocytopenia (platelet count usually <50 x 10⁹/L), and all are expected to develop nephropathy and severe hearing loss before age 40 years. Moreover, nephropathy usually progresses rapidly to ESRD in these individuals.
• The p.Asp1424His substitution is associated with an intermediate-to-high risk of developing extrahematologic manifestations over time. All individuals with this variant are expected to develop hearing loss by age 60 years; most affected individuals develop kidney disease before age 60 years; the risk for cataracts is higher than in those with other genotypes.
• Pathogenic variants encoding the residues at the interface between the SH3-like motif and the upper 50-kd subdomain of the head domain or those resulting in substitutions of the arginine residue 1165 are associated with a high risk for hearing loss (all are expected to develop hearing loss before age 60 years) and a low risk for nephropathy and cataract.
• The p.Asp1424Asn and p.Glu1841Lys substitutions, as well as the nonsense or frameshift pathogenic variants resulting in alterations of the carboxy-terminal nonhelical tailpiece of the MYH9 protein, are associated with low risk of developing the manifestations that develop over time; thus, macrothrombocytopenia usually remains the only clinically relevant disease feature throughout life [Pecci et al 2014a].

To date, no significant genotype-phenotype correlations have been identified for the occurrence of elevated liver enzyme levels [Pecci et al 2012].

Penetrance

Penetrance is complete for the following congenital findings:

• Platelet macrocytosis with giant platelets
• Aggregates of the MYH9 proteins in neutrophils

Except for a very few individuals in whom platelet count was just above the conventional cut-off value for thrombocytopenia (150 x 10⁹/L), thrombocytopenia is a congenital manifestation of the disease.

Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes.

Nomenclature

In the past, the conditions now collectively referred to as MYH9-RD were known as Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, Sebastian syndrome (Sebastian platelet syndrome), and autosomal dominant deafness 17 (DFNA17). The first four phenotypes, all characterized by macrothrombocytopenia with giant platelets, were classified on the basis of the presence of Döhle-like bodies on conventional staining of blood smears and different combinations of the other manifestations of MYH9-RD (see Table 3). DFNA17 was initially described as a nonsyndromic sensorineural hearing loss deriving from the single NM_002473.5:c.2114G>A (p.Arg705His) pathogenic variant [Lalwani et al 2000] (see also Hereditary Hearing Loss and Deafness Overview). However, subsequent investigations showed that individuals who are heterozygous for the p.Arg705His substitution present other manifestations typical of MYH9-RD along with hearing loss [Saposnik et al 2014, Verver et al 2015].

Table 3.

MYH9-Related Disease: Formerly Used Terminology

Prevalence

MYH9-RD is considered a rare disease. The Italian Registry for MYH9-RD includes 225 Italian affected individuals, indicating that the prevalence of the disorder in Italy is at least 3.75:1,000,000. Because mild forms are often discovered incidentally and severe forms are often misdiagnosed as other disorders, the actual prevalence is expected to be higher. Of note, other estimates – based on the frequency of MYH9 loss-of-function pathogenic variants in the EXAC database– suggest a much higher prevalence (~1:20,000-25,000) [Fernandez-Prado et al 2019].

MYH9-RD has been diagnosed worldwide, and there is no evidence of variation in prevalence across different populations.

Acquired Thrombocytopenia

Idiopathic (autoimmune) thrombocytopenic purpura (ITP). Differentiating between MYH9-RD and ITP (the most frequent form of acquired thrombocytopenia) is challenging and individuals with MYH9-RD are frequently misdiagnosed with ITP. Misdiagnosis with ITP often leads to treatments (immunosuppressive drugs and splenectomy) that are not only ineffective in individuals with MYH9-RD but also potentially harmful. For instance, among individuals enrolled in the Italian Registry for MYH9-RD, about 60% of index cases had received a previous diagnosis of ITP and 30% received inappropriate treatments, including splenectomy [Pecci et al 2018].

If the genetic origin of thrombocytopenia is not obvious because a family history is absent or unclear, the following findings on microscopic evaluation of peripheral blood slides are a simple and effective way to distinguish individuals with MYH9-RD from those with ITP [Noris et al 2014a]:

• Platelets are significantly larger in persons with MYH9-RD than in those with ITP: a mean platelet diameter >3.7 µm distinguishes MYH9-RD from ITP with 86% sensitivity and 87% specificity.
• More than 40% of platelets >3.9 µm (i.e., about half the diameter of a red blood cell) distinguishes MYH9-RD from ITP with 85% sensitivity and 87% specificity.

Assay of immunofluorescence staining of MYH9 protein distribution in neutrophils can also be used to differentiate MYH9-RD from ITP (see Diagnosis, Suggestive Findings). Molecular genetic testing provides confirmation of the diagnosis of MYH9-RD.

Inherited Thrombocytopenia

Table 4 summarizes the main forms of inherited thrombocytopenia with platelet macrocytosis (inherited macrothrombocytopenias) that should, therefore, be considered in the differential diagnosis of MYH9-RD.

Note: All congenital macrothrombocytopenias are very rare disorders.

Table 4.

Inherited Macrothrombocytopenias in the Differential Diagnosis of MYH9-Related Disease

Hereditary Nephritis

Alport syndrome. The spectrum of renal involvement in Alport syndrome ranges from isolated non-progressive hematuria to progressive nephropathy characterized by hematuria, proteinuria, and chronic kidney disease and end-stage renal disease. Affected individuals often have sensorineural hearing loss and characteristic ocular abnormalities. Rare individuals have associated aortic disease or diffuse leiomyomatosis. Alport syndrome is caused by pathogenic variants in COL4A3, COL4A4, or COL4A5 and can be transmitted in an X-linked, autosomal dominant, or autosomal recessive manner.

Platelet defects have not been described in Alport syndrome. Therefore, whenever nephropathies are associated with macrothrombocytopenia, MYH9-RD should be strongly considered.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MYH9-RD, the evaluations summarized in Table 5 are recommended at the time of diagnosis.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with MYH9-Related Disease

Treatment of Manifestations

Multidisciplinary management by different specialists including hematologists or internists with expertise in hemostasis, nephrologists, otolaryngologists, and ophthalmologists is recommended.

Table 6.

Treatment of Manifestations in Individuals with MYH9-Related Disease

Surveillance

Table 7.

Recommended Surveillance for Individuals with MYH9-Related Disease

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

It is appropriate to clarify the status of all first-degree relatives of an affected individual in order to establish: (1) appropriate management (including follow-up evaluations, treatment, and surveillance) and (2) awareness of agents and circumstances that should be avoided.

Evaluations to clarify the status of at-risk family members include:

• Examination of peripheral blood smear to search for platelet macrocytosis, assessment of platelet count, and immunofluorescence search for aggregates of the MYH9 protein;
• Molecular genetic testing if the MYH9 pathogenic variant has been identified in an affected family member.

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

Pregnancy Management

Deliveries should be managed as they are in women with other forms of thrombocytopenia. (Note that MYH9-RD is not usually associated with defects of platelet function.) As expected, severe thrombocytopenia and previous history of severe bleeding are associated with a higher incidence of delivery-related bleeding. In general, a platelet count of ≥50 x 10⁹/L is recommended for delivery. Infants born vaginally to women with severe thrombocytopenia are considered at increased risk for neonatal intracranial bleeding [Noris et al 2014b].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

MYH9-related disease (MYH9-RD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 65% of probands diagnosed with MYH9-RD have an affected parent.
• An individual with MYH9-RD may have the disorder as the result of a de novo MYH9 pathogenic variant. About 35% of probands represent simplex cases (i.e., a single occurrence in a family) [Savoia et al 2010]; most of these individuals have the disorder as the result of a de novo pathogenic variant [Pecci et al 2108].
• If neither parent of the proband is known to have MYH9-RD, the following evaluations are recommended for the parents in order to confirm their status and to allow reliable recurrence risk counseling:
  • Molecular genetic testing for the MYH9 pathogenic variant identified in the proband;
  • If the causative pathogenic variant has not been identified in the proband or a mild phenotype resulting from potential somatic mosaicism is suspected in a parent, appropriate hematologic testing (e.g., evaluation of platelet number and size and distribution of the MYH9 protein in neutrophils; see Diagnosis) should be considered.
• If the pathogenic variant found in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Both germline mosaicism and somatic mosaicism including the germline have been reported [Kunishima et al 2005, Kunishima et al 2009, Kunishima et al 2014]. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
    Note: A parent with somatic mosaicism for an MYH9 pathogenic variant may be mildly/minimally affected. In two families, apparently healthy parents of probands with typical MYH9-RD had de novo somatic/germline pathogenic variants with 14% or 24% of neutrophils with MYH9 aggregates but not thrombocytopenia [Kunishima et al 2005, Kunishima et al 2014]. In another family, the father of a proband with a severe syndromic phenotype had only mild macrothrombocytopenia associated with somatic mosaicism [Gresele at al 2013].
• The family history of some individuals diagnosed with MYH9-RD may appear to be negative because of failure to recognize the disorder in family members and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband and/or appropriate hematologic testing has been performed.

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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. A sib who inherits an MYH9 pathogenic variant may have a different phenotype (within the spectrum of MYH9-RD) than the proband.
• If the proband has a known MYH9 pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or both parents have normal results on hematologic testing, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism [Kunishima et al 2005, Kunishima et al 2009, Kunishima et al 2014].

Offspring of a proband. Each child of an individual with MYH9-RD has a 50% chance of inheriting the MYH9 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MYH9 pathogenic variant and/or is known to be 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 and Preimplantation Genetic Testing

Once the MYH9 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MYH9 encodes myosin-9, a protein of 1960 amino acids also known as the heavy chain of the non-muscle myosin IIA. Myosin-9 dimerizes and assembles with two essential and two regulatory light chains to constitute a hexameric molecule, the non-muscle myosin IIA (NMMIIA). NMMIIA assembles into functional bipolar filaments, which – interacting with actin – generate the mechanical force necessary for a variety of cellular processes, including motility and migration, cytokinesis, shape maintenance and change, and polarization.

Pathogenesis of the manifestations of MYH9-related disease is only partially understood. Macrothrombocytopenia results from defective production of platelets from megakaryocytes, their bone marrow precursors. In particular, the platelet phenotypes result from defects of the latest events of platelet biogenesis – that is, the formation and release of platelets from mature megakaryocytes. At the end of their maturation process, megakaryocytes form platelets through the extension of long and thin cellular protrusions, called proplatelets, that protrude through the lumen of bone marrow vessels and release platelets directly into the bloodstream from their free ends (the so-called tips).

NMMIIA is dispensable for megakaryocyte production and maturation, but has a key role in the extension of proplatelets. In fact, megakaryocytes of individuals with MYH9-RD, as well as those of mouse models of the disease, present few proplatelets, with reduced branching and very large tips, resulting in defective platelet release as well as platelet macrocytosis [Pecci et al 2018]. Moreover, MYH9 pathogenic variants may also impair migration of megakaryocytes within the bone marrow toward the marrow vessels, the site of platelet release; this mechanism can contribute to reduced platelet production [Pal et al 2020].

Kidney damage is thought to mainly result from defective function of the podocytes, highly specialized epithelial cells of the renal glomerular filtration barrier. Investigations of mouse models of MYH9-RD showed signs of podocyte damage, such as effacement of their foot processes with loss of the filtration slit between neighboring foot processes. These alterations resemble those observed in the few kidney biopsies of individuals with MYH9-RD analyzed to date. Moreover, in vitro studies demonstrated that MYH9 pathogenic variants induce profound alteration in the structure and functions of the cytoskeleton of podocytes that are likely to cause alteration of the kidney filtration barrier, proteinuria, and, therefore, progressive kidney disease [Pecci et al 2018].

The mechanisms of hearing loss are poorly understood. However, the hearing defect is likely to derive from alteration of the functions of the hair cells of the cochlea of the inner ear – that is, the cells specialized in converting the sound stimulus into electric signals directed to the brain.

Pathogenesis of the other phenotypes of MYH9-RD is unknown [Pecci et al 2018].

Mechanism of disease causation. Because MYH9-RD 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 pathogenic variants.

MYH9-specific laboratory technical considerations. MYH9 comprises 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.

The spectrum of the MYH9 pathogenic variants responsible for MYH9-related disease is mainly represented by missense variants or small in-frame deletions/insertions, most of which are identified in a few hot spots (exons 2, 17, 25, 26, 27, 31, and 39). The nonsense and frameshift pathogenic variants affect exclusively the last coding exon of MYH9 (exon 41).

Moreover, almost 70% of affected individuals have pathogenic variants involving only six residues: Ser96 or Arg702 of the head domain; and Arg1165, Asp1424, Glu1841, or Arg1933 of the tail domain [Pecci et al 2018].

Table 8.

Notable MYH9 Pathogenic Variants

Author Notes

Alessandro Pecci works as a physician and researcher at the IRCCS Policlinico San Matteo Foundation and the University of Pavia, Pavia, Italy. His research interests focus on hemostasis and thrombosis, ranging from clinical to basic research. He is particularly interested in clinical aspects, management and pathogenetic mechanisms of inherited thrombocytopenias. Email: ti.vpinu@iccep.ordnassela

Author History

Carlo L Balduini, MD; University of Pavia (2008-2015)
Alessandro Pecci, MD, PhD (2015-present)
Anna Savoia, PhD (2008-present)

Revision History

• 18 February 2021 (bp) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 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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