Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Abstract Context: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. Objective: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. Case Presentation: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4+/CD25+ and CD25high/FoxP3+ cells were diminished, whereas an unusual CD25−/FoxP3+ population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. Results: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. Conclusion: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.

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Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy

Cardiology ◽

10.1159/000447422 ◽

2016 ◽

Vol 136 (1) ◽

pp. 10-14 ◽

Cited By ~ 5

Author(s):

Ji-Shi Liu ◽

Liang-Liang Fan ◽

Hao Zhang ◽

Xiaoxian Liu ◽

Hao Huang ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Nonsense Mutation ◽

Novel Mutations ◽

Chinese Families ◽

Structure Changes ◽

Whole Exome ◽

Gene Filtering

Objectives: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. Methods: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations. Sanger sequencing was applied to confirm the mutation cosegregation in the affected families. Results: A nonsense mutation (c.12325C>T/p.R4109X) and a missense mutation (c.17755G>C/p.G5919R) of TTN were identified in 2 Chinese DCM families, respectively. Both mutations were cosegregated in all affected members of both families. The nonsense mutation is predicted to result in a truncated TTN protein and the missense mutation leads to a substitution of glycine by arginine. Both variants may cause the structure changes of titin protein. Conclusions: We employed WES to detect the mutations of DCM patients and identified 2 novel mutations. Our study expands the spectrum of TTN mutations and offers accurate genetic testing information for DCM patients who are still clinically negative.

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Whole-exome sequencing identified compound heterozygous variants in the TTN gene causing Salih myopathy with dilated cardiomyopathy in an Iranian family

Cardiology in the Young ◽

10.1017/s1047951121004455 ◽

2021 ◽

pp. 1-6

Author(s):

Mohammad Mahdavi ◽

Neda Mohsen-Pour ◽

Majid Maleki ◽

Mahshid Hesami ◽

Niloofar Naderi ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Molecular Diagnostic ◽

Metabolic Parameter ◽

Compound Heterozygous ◽

Formidable Challenge ◽

Whole Exome ◽

Iranian Family ◽

Compound Heterozygous Variants

Abstract Background: Salih myopathy, characterised by both congenital myopathy and fatal dilated cardiomyopathy, is an inherited muscle disorder that affects skeletal and cardiac muscles. TTN has been identified as the main cause of this myopathy, the enormous size of this gene poses a formidable challenge to molecular genetic diagnostics. Method: In the present study, whole-exome sequencing, cardiac MRI, and metabolic parameter assessment were performed to investigate the genetic causes of Salih myopathy in a consanguineous Iranian family who presented with titinopathy involving both skeletal and heart muscles in an autosomal recessive inheritance pattern. Results: Two missense variants of TTN gene (NM_001267550.2), namely c.61280A>C (p. Gln20427Pro) and c.54970G>A (p. Gly18324Ser), were detected and segregations were confirmed by polymerase chain reaction-based Sanger sequencing. Conclusions: The compound heterozygous variants, c.61280A>C, (p. Gln20427Pro) and c.54970G>A, (p. Gly18324Ser) in the TTN gene appear to be the cause of Salih myopathy and dilated cardiomyopathy in the family presented. Whole-exome sequencing is an effective molecular diagnostic tool to identify the causative genetic variants of large genes such as TTN.

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