Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects

Durbin, Matthew D.; Cadar, Adrian G; Williams, Charles H.; Guo, Yan; Bichell, David P.; Su, Yan; Hong, Charles C.

doi:10.1007/s00246-017-1650-5

Cited by 31 publications

(20 citation statements)

References 44 publications

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“…Hinton et al reported a set of monozygotic twins, one with BAV and the other with HLHS [3]. Pathogenic variants in other genes, such as NOTCH1, cause a spectrum of aortic valve abnormalities, including both BAV [13] and HLHS [28]. Based on observation alone, we cannot definitively prove that BAV and HLHS co-segregate within the family through a common genetic defect.…”

Section: Discussionmentioning

confidence: 87%

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype

Cheng

Neufeld-Kaiser

Byers

et al. 2020

BMC Cardiovasc Disord

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Introduction: Hypoplastic left heart syndrome (HLHS) is a rare but devastating congenital heart defect (CHD) accounting for 25% of all infant deaths due to a CHD. The etiology of HLHS remains elusive, but there is increasing evidence to support a genetic cause for HLHS; in particular, this syndrome is associated with abnormalities in genes involved in cardiac development. Consistent with the involvement of heritable genes in structural heart abnormalities, family members of HLHS patients have a higher incidence of both left-and right-sided valve abnormalities, including bicuspid aortic valve (BAV). Case presentation: We previously described (Am J Med Genet A 173:1848-1857, 2017) a 4-generation family with a 6q25.1 microdeletion encompassing TAB2, a gene known to play an important role in outflow tract and cardiac valve formation during embryonic development. Affected adult family members have short stature, dysmorphic facial features, and multiple valve dysplasia, including BAV. This follow-up report includes previously unpublished details of the cardiac phenotype of affected family members. It also describes a baby recently born into this family who was diagnosed prenatally with short long bones, intrauterine growth restriction (IUGR), and HLHS. He was the second family member to have HLHS; the first died several decades ago. Postnatal genetic testing confirmed the baby had inherited the familial TAB2 deletion. Conclusions: Our findings suggest TAB2 haploinsufficiency is a risk factor for HLHS and expands the phenotypic spectrum of this microdeletion syndrome. Chromosomal single nucleotide polymorphism (SNP) microarray analysis and molecular testing for a TAB2 loss of function variant should be considered for individuals with HLHS, particularly in those with additional non-cardiac findings such as IUGR, short stature, and/or dysmorphic facial features.

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Section: Discussionmentioning

confidence: 87%

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype

Cheng

Neufeld-Kaiser

Byers

et al. 2020

BMC Cardiovasc Disord

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“…Formalin fixed heart tissue samples from human patients with HLHS were reported to contain protein mutations in Hand1 (Reamon‐Buettner et al ; Wang et al ). However, further analysis from fresh frozen tissue from HLHS patients did not recapitulate this finding (Esposito et al ; Durbin et al ). Analysis of the molecular consequences of this mutation in mice was conducted by generating a transgenic animal with mutant Hand1 allele that has a nucleotide deletion at codon 126, causing a frameshift mutation leading to termination after 13 amino acids with a stop flox cassette that allows conditional activation (Firulli et al ).…”

Section: Hand Factors In Cardiomyocytesmentioning

confidence: 99%

Hand Factors in Cardiac Development

George

Firulli

2018

The Anatomical Record

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Congenital heart defects account for 1% of infant mortality and 10% of in-utero deaths. As the vertebrate embryo develops, multiple tissue types develop in tandem to morphologically pattern the functional heart. Underlying cardiac development is a network of transcription factors known to tightly control these morphological events. Members of the Twist family of basic helix-loop-helix (bHLH) transcription factors, Hand1 and Hand2, are essential to this process. The expression patterns and functional role of Hand factors in neural crest cells (NCC), endocardium, myocardium, and epicardium is indicative of their importance during cardiogenesis; however, to date, an extensive understanding of the transcriptional targets of Hand proteins and their overall mechanism of action remain unclear. In this review, we summarize the recent findings that further outline the crucial functions of Hand factors during heart development and in post-natal heart function.

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“…It is hypothesized that secondary heart field development is regulated by signaling pathways including Wnt, Fgf, Tgfβ, and Notch (Rochais, Mesbah, & Kelly, ). Interestingly, a case of hypoplastic left heart syndrome, who had a NOTCH1 mutation, was reported to have an aunt with HRHS (Durbin et al, ) suggesting that our current understanding of the mechanisms underlying the genetic signaling pathways and their role in these defects is incomplete. It is known that several genes and transcription factors, including Nkx2.5 , Hand2 , Tbx5 , Isl1 , and Foxh1 are reported to have a pattern of high expression in the secondary heart field (Black, ; Steimle & Moskowitz, ; Su et al, ).…”

Section: Discussionmentioning

confidence: 99%

Copy number variants in hypoplastic right heart syndrome

Giannakou

Sicko

Kay

et al. 2018

American J of Med Genetics Pt A

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Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases.ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.

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Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects

Cited by 31 publications

References 44 publications

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype

6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype

Hand Factors in Cardiac Development

Copy number variants in hypoplastic right heart syndrome

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