Holt‐Oram syndrome in four half‐siblings with unaffected parents: brief clinical report

Braulke, I.; Herzog, S.; Thies, Ulrike; Zoll, Barbara

doi:10.1111/j.1399-0004.1991.tb03021.x

Cited by 13 publications

(4 citation statements)

References 11 publications

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“…On the other hand, PreP as an apparently single anomaly, could be the only visible defect of some of the recognized autosomal dominant conditions such as the Holt Oram syndrome, where a mild and therefore overlooked heart defect could lead to its misdiagnosis. To our knowledge, advanced PA has not been mentioned in association with Holt Oram, although a relationship could be indirectly inferred (Barisic et al, 2014; Braulke et al, 1991). In a study on Townes Brocks, another syndrome of autosomal dominant inheritance that includes anus atresia and PreP among its features, Böhm et al (2006) demonstrated the paternal origin of the mutation in 14 of their 16 cases, without an obvious PA effect.…”

Section: Discussionmentioning

confidence: 93%

Paternal age and risk for selected birth defects in a large South American sample

Gili,

Rittler,

Heisecke

et al. 2023

Birth Defects Research

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BackgroundThe relationship between maternal age (MA) and birth defects (BD) has been extensively studied while much less research, mostly with discordant results, has focused on the risk of paternal age (PA) for BD. Furthermore, no consensus has been reached on the best way to control the association of PA with MA.ObjectivesThe aim of the study was to evaluate the risk of PA increase, at 1‐year intervals, for selected BD, especially controlling for the confounding effect of MA.MethodsThe sample comprised of 27,944 liveborns presenting 1 of 18 selected isolated BD. Conditional logistic regressions were applied to evaluate the risk of advanced PA and its yearly increase, adjusting by MA and other variables.ResultsOf the 18 analyzed BD, only the risk for preaxial polydactyly (PreP) showed a significant association with increasing PA, while advanced MA was of low risk. For esophageal and anal atresia, associations with both PA and MA increases were observed.ConclusionsResults support the hypothesis of advanced PA as a risk factor for PreP and helps clarify the so far unexplained nonrandom association between this defect and Down syndrome.

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Section: Discussionmentioning

confidence: 93%

Paternal age and risk for selected birth defects in a large South American sample

Gili,

Rittler,

Heisecke

et al. 2023

Birth Defects Research

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“…Also mutations located outside the T-box domain show a similar genotype-phenotype correlation, determining predominantly heart or limb defects according to the mutation. Germinal mosaicism has also been reported in one case report in which an unaffected man fathered 4 offspring with HOS by 3 different women [ 116 ]. Although no other cases have been described in the literature, we have found a family with 2 affected offspring from unaffected parents.…”

Section: Mendelian Formsmentioning

confidence: 88%

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Elmakky¹,

Stanghellini²,

Landi³

2015

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Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.

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“…It is considered 100% penetrant with varying expressivity in the heart and upper extremity [ 10 ]. However, incomplete penetrance [ 11 ], lack of penetrance [ 12 ], somatic mosaicism [ 12 ], and probable germinal mosaicism [ 13 ] have also been reported for this disease. The majority of the patients suffer from this syndrome due to de novo mutations [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of deleterious single nucleotide polymorphism (SNP)s in the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach

Mahfuz¹,

Khan²,

Deb³

et al. 2021

Biochemistry and Biophysics Reports

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T-box transcription factor 5 gene ( TBX5 ) encodes the transcription factor TBX5, which plays a crucial role in the development of heart and upper limbs. Damaging single nucleotide variants in this gene alter the protein structure, disturb the functions of TBX5, and ultimately cause Holt-Oram Syndrome (HOS). By analyzing the available single nucleotide polymorphism information in the dbSNP database, this study was designed to identify the most deleterious TBX5 SNPs through in silico approaches and predict their structural and functional consequences. Fifty-eight missense substitutions were found damaging by sequence homology-based tools: SIFT and PROVEAN, and structure homology-based tool PolyPhen-2. Various disease association meta-predictors further scrutinized these SNPs. Additionally, conservation profile of the amino acid residues, their surface accessibility, stability, and structural integrity of the native protein upon mutations were assessed. From these analyses, finally 5 SNPs were detected as the most damaging ones: [rs1565941579 (P85S), rs1269970792 (W121R), rs772248871 (V153D), rs769113870 (E208D), and rs1318021626 (I222N)]. Analyses of stop-lost, nonsense, UTR, and splice site SNPs were also conducted. Through integrative bioinformatics analyses, this study has identified the SNPs that are deleterious to the TBX5 protein structure and have the potential to cause HOS. Further wet-lab experiments can validate these findings.

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Holt‐Oram syndrome in four half‐siblings with unaffected parents: brief clinical report

Cited by 13 publications

References 11 publications

Paternal age and risk for selected birth defects in a large South American sample

Paternal age and risk for selected birth defects in a large South American sample

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Identification of deleterious single nucleotide polymorphism (SNP)s in the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach

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