Heart‐hand syndrome <scp>IV</scp>: a second family with <i><scp>LMNA</scp></i>‐related cardiomyopathy and brachydactyly

Zaragoza, Michael V.; Hakim, Simin; Hoang, Van; Elliott, Alison M.

doi:10.1111/cge.12870

Cited by 19 publications

(22 citation statements)

References 4 publications

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“…However, majority of the LMNA-CM individuals are below the trend-line, which explains the aggregated average percent defective for LMNA-CM and LMNA-CM-A groups. From clinical data [ 4 , 9 , 10 ], we knew that the older patients in the cohort (LMNA-CM) developed heart disease later in life. Therefore, we plotted the difference between each patient’s cells’ dysmorphic nuclei percentage and the predicted value based on the control trend line (green arrow, Fig 4A ) against the age at which patients first presented with heart disease symptoms ( Fig 4B ).…”

Section: Resultsmentioning

confidence: 99%

“…Human fibroblast cells were collected from three families with different mutations of heterozygous LMNA splice-site mutation (c.357-2A>G) [ 4 ] (Family A); LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4 [ 10 ] (Family B); LMNA missense mutation (c.1003C>T, pR335W) in exon 6 [ 9 ] (Family C). Moreover, related individuals’ fibroblast cells in each family were collected as mutation-negative controls.…”

Section: Methodsmentioning

confidence: 99%

“…This is especially interesting as some nuclear envelope protein mutations lead to organ specific pathologies in patients. For example, there are a variety of LMNA mutations including heterozygous splice site, nonsense, and missense mutation, which cause diverse heart diseases with no other major pathologies [ 4 , 9 , 10 ]. Furthermore, even patients with the same mutation can exhibit a variety of heart disease symptoms with different presentation ages from 36–54 years [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations

et al. 2017

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Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high-throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice-site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method’s utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations

et al. 2017

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“…HOS is the most common heart-hand syndrome (defined by congenital heart defects associated with skeletal abnormalities of the upper limb) usually associated with an atrial septal defect (ASD). Uncommon subtypes of heart-hand syndrome are Tabatznik syndrome (type II; arrhythmias and brachytelephalangy) and Spanish variant (type III; arrhythmia and brachydactyly type C) and potential Slovenian type (type IV; arrhythmia, dilated cardiomyopathy, brachydactyly) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Holt-Oram Syndrome With Multiple Cardiac Abnormalities

et al. 2018

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Holt-Oram syndrome (HOS) is a rare monogenic disorder characterized by upper limb abnormalities, congenital heart defects and/or conduction abnormalities. It is determined by mutations of TBX5 gene and is inherited in an autosomal dominant manner. Penetrance is complete, but variable expressivity is present, which gives sometimes diagnostic difficulties. Our case is a young adult with a personal history of preaxial polydactyly operated in infancy, multiple cardiac malformations (atrial septal defect, bicuspid aortic valve, left ventricular non-compaction) and radiologic findings consistent with HOS. Family history is negative for HOS. In conclusion, we present a case of HOS diagnosed in the adult period to highlight the diagnostic problems for the proband and the family and the importance of an early diagnostic.

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“…The Identify and Annotate Variants (WES-HD) workflow and variant analysis tools for splicing effects were utilized to identify DNA variants. The lists of variants for each of the four family members were filtered in a step-wise approach to identify potential mutations and modifiers similar to the approach as described [ 21 , 22 ]. Candidate variants were identified as potentially deleterious single nucleotide variants (SNV) and insertion–deletion variants (indels) that were shared among the three affected family members (III-4, IV-3 and Patient 3) and not shared with the one individual unaffected at age 60 years old (IV-1).…”

Section: Methodsmentioning

confidence: 99%

Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene

Zaragoza

Nguyen

Widyastuti

et al. 2017

Cells

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Dupuytren’s disease (palmar fibromatosis) involves nodules in fascia of the hand that leads to flexion contractures. Ledderhose disease (plantar fibromatosis) is similar with nodules of the foot. While clinical aspects are well-described, genetic mechanisms are unknown. We report a family with cardiac disease due to a heterozygous LMNA mutation (c.736C>T, p.Gln246Stop) with palmar/plantar fibromatosis and investigate the hypothesis that a second rare DNA variant increases the risk for fibrotic disease in LMNA mutation carriers. The proband and six family members were evaluated for the cardiac and hand/feet phenotypes and tested for the LMNA mutation. Fibroblast RNA studies revealed monoallelic expression of the normal LMNA allele and reduced lamin A/C mRNAs consistent with LMNA haploinsufficiency. A novel, heterozygous missense variant (c.230T>C, p.Val77Ala) in the Asteroid Homolog 1 (ASTE1) gene was identified as a potential risk factor in fibrotic disease using exome sequencing and family studies of five family members: four LMNA mutation carriers with fibromatosis and one individual without the LMNA mutation and no fibromatosis. With a possible role in epidermal growth factor receptor signaling, ASTE1 may contribute to the increased risk for palmar/plantar fibromatosis in patients with Lamin A/C haploinsufficiency.

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Heart‐hand syndrome IV: a second family with LMNA‐related cardiomyopathy and brachydactyly

Cited by 19 publications

References 4 publications

Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations

Age of heart disease presentation and dysmorphic nuclei in patients with LMNA mutations

Holt-Oram Syndrome With Multiple Cardiac Abnormalities

Dupuytren’s and Ledderhose Diseases in a Family with LMNA-Related Cardiomyopathy and a Novel Variant in the ASTE1 Gene

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