Clinical characteristics.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.

Diagnosis/testing.

The diagnosis of EDMD is established in a proband with:

• A clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life); AND
• A hemizygous pathogenic variant in EMD or FHL1, a heterozygous pathogenic variant in LMNA, or (more rarely) biallelic pathogenic variants in LMNA identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment for cardiac arrhythmias, AV conduction disorders, congestive heart failure, including antiarrhythmic drugs, cardiac pacemaker, implantable cardioverter defibrillator; heart transplantation for the end stages of heart failure as appropriate; respiratory aids (respiratory muscle training, assisted coughing techniques, mechanical ventilation) as needed. Surgery to release contractures and manage scoliosis as needed; aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation; physical therapy and stretching to prevent contractures.

Surveillance: At a minimum, annual cardiac assessment (EKG, Holter monitoring, echocardiography); monitoring of respiratory function.

Agents/circumstances to avoid: Triggering agents for malignant hyperthermia, such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane); obesity.

Evaluation of relatives at risk: Molecular genetic testing if the pathogenic variant(s) in the family are known; clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known.

Genetic counseling.

EDMD is inherited in an X-linked, autosomal dominant, or, rarely, autosomal recessive manner.

• XL-EDMD. If the mother of a proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous. Heterozygous females are usually asymptomatic but are at risk of developing a cardiac disease, progressive muscular dystrophy, and/or an EDMD phenotype.
• AD-EDMD. 65% of probands with AD-EDMD have a de novo LMNA pathogenic variant. Each child of an individual with AD-EDMD has a 50% chance of inheriting the pathogenic variant.
• AR-EDMD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for EDMD are possible.

Suggestive Findings

Emery-Dreifuss muscular dystrophy (EDMD) should be suspected in individuals with the following triad [Emery 2000]:

• Early contractures of the elbow flexors, Achilles tendons (heels), and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the entire spine
• Slowly progressive wasting and weakness typically of the humero-peroneal/scapulo-peroneal muscles in the early stages
• Cardiac disease with conduction defects and arrhythmias
  • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG.
  • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation.

Age of onset. Onset usually occurs between age five and ten years, rarely before age five years.

Family history. May be positive (autosomal dominant, X-linked, or, rarely, autosomal recessive). However, simplex cases as a result of de novo genetic events are not rare.

Note: Diagnosis guidelines have been published [Emery 1997, Bonne et al 2002b, Madej-Pilarczyk 2018].

Establishing the Diagnosis

The diagnosis of EDMD is established in a proband with a clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life) and a hemizygous pathogenic (or likely pathogenic) variant in EMD or FHL1, a heterozygous pathogenic (or likely pathogenic) variant in LMNA, or (more rarely) biallelic pathogenic (or likely pathogenic) variants in LMNA identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, 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. Because the phenotype of EDMD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical features in whom the diagnosis of EDMD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Genotype-Phenotype Correlations

EMD. Intra- and interfamilial variability in the severity of clinical features are observed. However,

• Null variants, the majority of EMD pathogenic variants that result in complete absence of emerin expression, tend to have a more severe phenotype [Muntoni et al 1998, Hoeltzenbein et al 1999, Canki-Klain et al 2000, Ellis et al 2000].
• Missense variants associated with decreased or normal amounts of emerin and result in a milder phenotype [Yates et al 1999].

LMNA. Marked intra- and interfamilial variability is observed for the same LMNA pathogenic variant [Bécane et al 2000, Bonne et al 2000, Mercuri et al 2005, Carboni et al 2010]. For example, within the same family the same pathogenic variant can lead to AD-EDMD, LGMD1B, or isolated DCM-CD (i.e., laminopathies involving striated muscle) [Bécane et al 2000, Brodsky et al 2000, Granger et al 2011]. However,

• Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type) while frameshift variants have been associated with later-onset muscle symptoms of limb girdle type [Benedetti et al 2007].
• Homozygous and compound heterozygous pathogenic variants appear to lead to a more severe muscular phenotype [Raffaele Di Barletta et al 2000, Brown et al 2001, Scharner et al 2011, Jimenez-Escrig et al 2012].
• Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin A/C lead to EDMD [Krimm et al 2002].

EMD and LMNA. Severe EDMD has been reported in individuals with pathogenic variants in both EMD and LMNA [Muntoni et al 2006, Meinke et al 2011]. A range of clinical presentations (i.e., CMT2, CMT2-EDMD, and isolated cardiomyopathy) were found in a large family in which pathogenic variants in EMD and LMNA cosegregate [Ben Yaou et al 2007, Meinke et al 2011].

FHL. No definite genotype-phenotype correlations for FHL1 have been identified.

Penetrance

Five LMNA pathogenic variants were reported with reduced penetrance in families with AD-EDMD or other LMNA-related disorders [Vytopil et al 2002, Rankin et al 2008].

Prevalence

The prevalence of XL-EDMD has been estimated at 0.13:100,000-0.2:100,000 [Norwood et al 2009]. This form of EDMD accounts for approximately 10% of the total cases of EDMD (see Table 1). Therefore, the prevalence of EDMD of all types is estimated to be 1.3:100,000-2:100,000.

EMD

The disorders caused by pathogenic variants in EMD are called "emerinopathies" and affect striated muscles:

• X-linked limb-girdle muscular dystrophy (LGMD) phenotype caused by pathogenic variants in EMD; rarely reported [Ura et al 2007, Fanin et al 2009]
• X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [Ben Yaou et al 2007, Karst et al 2008]

FHL1

FHL1-related diseases include three allelic disorders characterized by the presence of reducing bodies detected on histopathology:

• Reducing body myopathy [Schessl et al 2008]
• X-linked scapuloperoneal myopathy [Quinzii et al 2008]
• Some cases of rigid spine syndrome [Shalaby et al 2008]

Other allelic FHL1-related diseases:

• X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to FHL1-related EDMD) [Windpassinger et al 2008]
• X-linked hypertrophic cardiomyopathy [Gueneau et al 2009, Friedrich et al 2012]

LMNA

The disorders caused by pathogenic variants in LMNA are called "laminopathies."

Disorders of striated muscle (See Note.)

• LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [van der Kooi et al 1996, Muchir et al 2000]
• CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [Fatkin et al 1999, Bécane et al 2000]
• Autosomal dominant dilated cardiomyopathy (DCM) with apical left ventricular aneurysm without atrio-ventricular block [Forissier et al 2003]; DCM with early atrial fibrillation [Sébillon et al 2003]; DCM with left ventricular non-compaction [Hermida-Prieto et al 2004]
• Arrhythmogenic right ventricular cardiomyopathy [Quarta et al 2012]
• Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [Charniot et al 2003]
• Neurogenic variant of EDMD [Walter et al 2005]
• LMNA-related congenital muscular dystrophy (L-CMD) [Quijano-Roy et al 2008]

Note: (1) These may not truly be allelic disorders because the phenotype overlaps with EDMD. See comments in Genotype-Phenotype Correlations. (2) Laminopathies affecting striated muscles are important to recognize because of the severity of the dilated cardiomyopathy associated with conduction/rhythm (DCM-CD) disorders, and the high frequency of sudden death [van Berlo et al 2005]. (3) See also Dilated Cardiomyopathy Overview.

Disorders of peripheral nerve

• CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the pathogenic founder variant p.Arg298Cys [De Sandre-Giovannoli et al 2002] (See Charcot-Marie-Tooth Hereditary Neuropathy Overview.)
• Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy, and leukonychia [Goizet et al 2004].
• Autosomal dominant CMT2 associated with myopathy [Benedetti et al 2005].

Disorders of fatty tissues. Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD) [Shackleton et al 2000]. The majority of FPLD cases are caused by LMNA pathogenic variants affecting arginine codon 482, leading to several amino acid substitutions [Bonne et al 2003]. Isolated metabolic manifestations without lipodystrophy have been also reported [Young et al 2005, Decaudain et al 2007].

Disorders involving several tissues

• Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [Garg et al 2002, van der Kooi et al 2002]
• Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder pathogenic variants are reported in MAD (p.Arg527His) [Novelli et al 2002].
• Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [Caux et al 2003]
• Hutchinson-Gilford progeria syndrome (HGPS) (autosomal dominant). Pathogenic variants in codon 608 are associated with HGPS [De Sandre-Giovannoli et al 2003, Eriksson et al 2003].
• Atypical Werner syndrome (autosomal dominant) [Chen et al 2003]
• Restrictive dermopathy [Navarro et al 2004]
• Progeria, arthropathy, and calcinosis of tendons [Van Esch et al 2006]
• Heart-hand syndrome, Slovenian type [Renou et al 2008]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Emery-Dreifuss muscular dystrophy (EDMD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Although malignant hyperthermia susceptibility has not been described in EDMD, it is appropriate to anticipate a possible malignant hyperthermia reaction and to avoid triggering agents such as depolarizing muscle relaxants (succinylcholine) and volatile anesthetic drugs (halothane, isoflurane). Other anesthetic precautions must be considered [Aldwinckle & Carr 2002].

Body weight should be monitored, as affected individuals may be predisposed to obesity.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with EDMD because of the high risk for cardiac complications (including sudden death) associated with EDMD. Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures [Manilal et al 1998, Bécane et al 2000, Boriani et al 2003, Maioli et al 2007, Gueneau et al 2009, Scharner et al 2011, Jimenez-Escrig et al 2012, Stallmeyer et al 2012, Madej-Pilarczyk et al 2018]. Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known.

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

Pregnancy Management

In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Pregnancy management is challenging, with very limited literature addressing the issue. Caesarean section delivery may be required. Referral of an affected pregnant woman to a specialized obstetric unit in close collaboration with a cardiologist is recommended for optimal pregnancy outcome.

Therapies Under Investigation

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

Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked (XL-EDMD), an autosomal dominant (AD-EDMD), or, rarely, an autosomal recessive (AR-EDMD) manner.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disease nor will he be hemizygous for the EMD or FHL1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected son and no other affected relatives and if the EMD or FHL1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. One instance of germline mosaicism in XL-EDMD has been reported [Manilal et al 1998].
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo EMD or FHL1 pathogenic variant, in which case the mother is not a heterozygote. The frequency of de novo pathogenic variants is thought to be less than one third, although no published data from large series are available [Wulff et al 1997, Yates & Wehnert 1999].
• Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [Gueneau et al 2009, Knoblauch et al 2010]. (See Management, Evaluation of Relatives at Risk.)

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an EMD or FHL1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant are usually asymptomatic but are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [Gueneau et al 2009, Knoblauch et al 2010]. (See Evaluation of Relatives at Risk.)
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the EMD or FHL1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. Germline mosaicism has been reported in XL-EDMD [Manilal et al 1998].

Offspring of a proband. Affected males transmit the EMD or FHL1 pathogenic variant to:

• All of their daughters, who will be heterozygotes. Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [Gueneau et al 2009, Knoblauch et al 2010]. (See Evaluation of Relatives at Risk.)
• None of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their sex, may be at risk of being heterozygotes or of being affected.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the EMD or FHL1 pathogenic variant has been identified in the proband.

Note: Females heterozygous for an EMD or FHL1 pathogenic variant are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [Gueneau et al 2009, Knoblauch et al 2010]. (See Evaluation of Relatives at Risk.)

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with AD-EDMD have an affected parent.
• A proband with AD-EDMD often has the disorder as the result of a de novo LMNA pathogenic variant. Current unpublished data indicate that 65% of pathogenic variants are de novo [Author, personal observation].
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing and clinical evaluation – in particular, cardiac investigations.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported; its incidence is not known [Bonne et al 1999, Makri et al 2009].
• The family history of some individuals diagnosed with AD-EDMD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., molecular genetic testing and cardiac evaluation) have been performed on the parents of the proband. (See Evaluation of Relatives at Risk.)
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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%.
• If the LMNA pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the LMNA pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for AD-EDMD because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with AD-EDMD has a 50% chance of inheriting the LMNA pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or has the pathogenic variant, the parent's family members are at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are typically obligate heterozygotes (i.e., carriers of one LMNA pathogenic variant).
• Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [Jimenez-Escrig et al 2012]. (See Evaluation of Relatives at Risk.)

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [Jimenez-Escrig et al 2012]. (See Evaluation of Relatives at Risk.)

Offspring of a proband. The offspring of an individual with AR-EDMD are obligate heterozygotes for a pathogenic variant in LMNA.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an LMNA pathogenic variant.

Heterozygote detection. Molecular genetic testing for at-risk relatives requires prior identification of the LMNA pathogenic variants in the family.

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 pathogenic variant. When neither parent of a proband with AD-EDMD has the LMNA pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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, are heterozygotes, or are at risk of being heterozygotes.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible.

Molecular Pathogenesis

The genes EMD, LMNA, and FHL1 – pathogenic variants in which cause Emery-Dreifuss muscular dystrophy (EDMD) – encode proteins critical for the organization of the nuclear envelope. Although not entirely elucidated, two main mechanisms (not necessarily mutually exclusive) are thought to be involved in EDMD pathogenesis [Broers et al 2006, Worman & Bonne 2007, Worman et al 2009]:

• Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle
• Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells

Interactions of these nuclear envelope proteins with chromatin- and nuclear matrix-associated proteins are of particular interest. Both emerin and lamin A/C interact with nuclear actin, a component of the chromatin remodeling complex associated with the nuclear matrix, suggesting that either chromatin arrangement or gene transcription or both could be impaired in the disease [Maraldi et al 2002].

Acknowledgments

Authors are coordinators (GB, FL, RBY) of the French networks for rare diseases on "EDMD and other nuclear envelope pathologies," network supported by AFM (Association Française contre les Myopathies, grant #10722 and #12325). GB and RBY have been members of the European consortium "Euro-Laminopathies" supported by an EU-FP7 grant (#018690) and are currently members of SOLVE-RD, an European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, the Assistance Publique des Hôpitaux de Paris.

Author History

Rabah Ben Yaou, MD (2004-present)
Gisèle Bonne, PhD (2004-present)
France Leturcq, MD (2004-present)
Dominique Récan-Budiartha, MD; Hôpital Cochin (2004-2010)

Revision History

• 15 August 2019 (ha) Comprehensive update posted live
• 25 November 2015 (me) Comprehensive update posted live
• 17 January 2013 (me) Comprehensive update posted live
• 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for FHL1 mutations available clinically
• 15 June 2010 (me) Comprehensive update posted live
• 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically
• 26 April 2007 (me) Comprehensive update posted live
• 29 September 2004 (me) Review posted live
• 27 January 2004 (gb) Original submission

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