Three cases of isolated terminal deletion of chromosome 8p without heart defects presenting with a mild phenotype

Burnside, Rachel D.; Pappas, John; Sacharow, Stephanie; Applegate, Carolyn D.; Hamosh, Ada; Gadi, Inder K.; Jaswaney, Vikram; Keitges, Elisabeth A.; Phillips, Karen K.; Potluri, Venketaswara R.; Risheg, Hiba; Smith, Janice; Tepperberg, Jim; Schwartz, Stuart; Papenhausen, Peter

doi:10.1002/ajmg.a.35699

Cited by 22 publications

(20 citation statements)

References 29 publications

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“…When compared with overlapping distal 8p deletions that have been mapped using molecular methods (Burnside et al, Patient 3; Bosse et al, ; Giglio et al, Case 1) (Figure a; Supplementary Table SI), the proband in this family shares developmental delay and short stature as a child with two probands (Burnside et al, Patient 3; Bosse et al, ) and unsteady gait as a child with one (Burnside et al, , Patient 3) but differs in having CHD, sensorineural deafness, microcephaly, and no dysmorphic features. These are not features normally associated with distal 8p deletions that have a mild and variable phenotype that can be compatible with normal cognition (Gilmore, Cuskelly, Jobling, & Smith, ) or a normal phenotype (Reddy, ).…”

Section: Discussionmentioning

confidence: 99%

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

Bateman

Collinson

Bunyan

et al. 2017

American J of Med Genetics Pt A

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The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.

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Section: Discussionmentioning

confidence: 99%

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

Bateman

Collinson

Bunyan

et al. 2017

American J of Med Genetics Pt A

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“…As case 2 demonstrates, fetal anomalies can result from a number of chromosomal rearrangements, duplications and deletion syndromes. There are reports of individuals with small amounts of extra 8p material that are healthy, develop normally and have healthy children [4]. The abnormalities appear to include developmental delay, learning difficulties, hypotonia, heart defect and agenesis of the corpus callosum.…”

Section: Discussionmentioning

confidence: 99%

“…The microarray demonstrated an 8.10 MB terminal deletion of 8pTER to 8p23.1 and a 31.8 MB interstitial duplication of 8p23.1 to 8p11.1. Previously reported cases in this region include anomalies of the central nervous system, renal and cardiac systems [4]. Patients with this duplication also present with severe intellectual disability and multiple minor abnormalities [5].…”

Section: Case Reportmentioning

confidence: 99%

Understanding the Limitations of Circulating Cell Free Fetal DNA: An Example of Two Unique Cases

Clark-Ganheart

Iqbal

Brown

et al. 2014

J Clin Gynecol Obstet

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Circulating cell free fetal DNA (cffDNA) is an effective screening modality for fetal aneuploidy. We report two cases of false positive results. The first case involves a female, with self-reported Down syndrome. CffDNA returned positive for trisomy 18 leading to a maternal diagnosis of mosaicism chromosome 18 with normal fetal karyotype. The second case involves a patient with an anomalous fetal ultrasound and cffDNA positive for trisomy 13. Amniocentesis demonstrated a chromosome 8p duplication/deletion. False positive cffDNA may arise in clinical scenarios where diagnostic testing is clearly indicated. Practitioners should recognize the limitations of cffDNA.

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“…Two forms of DNA sequence-based markers, SNPs and simple sequence repeats (SSRs), predominate in contemporary genetic analysis [78,79]. The most studied molecular genetic markers, SNPs, are distributed over the whole genome [80].…”

Section: Molecular Genetic Biomarkersmentioning

confidence: 99%

Genomic translational research: Paving the way to individualized cardiac functional analyses and personalized cardiology

Pasipoularides

2017

International Journal of Cardiology

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For most of Medicine’s past, the best that physicians could do to cope with disease prevention and treatment was based on the expected response of an average patient. Currently, however, a more personalized/precise approach to cardiology and medicine in general is becoming possible, as the cost of sequencing a human genome has declined substantially. As a result, we are witnessing an era of precipitous advances in biomedicine and bourgeoning understanding of the genetic basis of cardiovascular and other diseases, reminiscent of the resurgence of innovations in physico-mathematical sciences and biology-anatomy-cardiology in the Renaissance, a parallel time of radical change and reformation of medical knowledge, education and practice. Now on the horizon is an individualized, diverse patient-centered, approach to medical practice that encompasses the development of new, gene-based diagnostics and preventive medicine tactics, and offers the broadest range of personalized therapies based on pharmacogenetics. Over time, translation of genomic and high-tech approaches unquestionably will transform clinical practice in cardiology and medicine as a whole, with the adoption of new personalized medicine approaches and procedures. Clearly, future prospects far outweigh present accomplishments, which are best viewed as a promising start. It is now essential for pluridisciplinary health care providers to examine the drivers and barriers to the clinical adoption of this emerging revolutionary paradigm, in order to expedite the realization of its potential. So, we are not there yet, but we are definitely on our way.

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Three cases of isolated terminal deletion of chromosome 8p without heart defects presenting with a mild phenotype

Cited by 22 publications

References 29 publications

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

Understanding the Limitations of Circulating Cell Free Fetal DNA: An Example of Two Unique Cases

Genomic translational research: Paving the way to individualized cardiac functional analyses and personalized cardiology

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