Neonatal Cyanosis Due to a Novel Fetal M-Hemoglobin: Hemoglobin F-M Circleville (Gγ63 His→Leu).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3806-3806
Author(s):  
Ferdane Kutlar ◽  
Richard Shell ◽  
Joan Atkin ◽  
Dedrey Elam ◽  
Leslie Holley ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Postnatal Period ◽  
De Novo Mutations ◽  
Reverse Phase Hplc ◽  
Hemoglobin F ◽  
The Family ◽  
Novel Variant ◽  
Hb S ◽  
Hemoglobin Variants

Abstract Neonatal cyanosis can result from a multitude of acquired and inherited causes. Cyanosis resulting from fetal M-Hemoglobin variants is a rare cause of this condition. In fact, to date, only two Gγ variants causing methemoglobinemia and cyanosis in the newborn have been reported. These are Hb F-M Osaka (Gγ63 His→Tyr) and Hb F-M Fort Ripley (Gγ92 His→Tyr). We report a novel fetal M-hemoglobin presenting with neonatal cyanosis. The propositus was a 1-day old Caucasian male admitted to the hospital because of cyanotic episodes. The patient had an O2 saturation of 85% on room air and required supplemental O2 during his 10-day hospitalization. The family history was significant for a 4-year old sister having a 5-day hospitalization after delivery for cyanosis. The sister required supplemental O2 for 4–5 months to maintain a satisfactory O2 saturation. Both parents were healthy and had no recollection of neonatal cyanosis or O2 requirement. The newborn screening for hemoglobinopathies reportedly showed Hb F, A, and a variant migrating between Hb S and Hb F. Cation exchange HPLC performed at 1-month of age revealed 68.4% Hb F; 17.5% Hb A, and 14.0% Hb X, eluting between Hb F and Hb A. Reverse phase HPLC showed only βA, αa, Gγ, and Aγ chains without any detectable abnormal chains. O2 affinity showed a P50 of 24.2mmHg (control 23.4mmHg). Sequencing of the PCR amplified Gγ gene revealed heterozygosity for a CAT→CTT mutation (His→Leu) at codon 63. (GenBank Acession # AY662983). This novel variant was named Hb F-Circleville [GγE7(63)His→Leu]. The M-hemoglobins arise from mutations in the conserved proximal (F8) or distal (E7) histidine residues, which are important heme contacts. Substitution of these residues lead to methemoglobinemia and cyanosis. Fetal Hb variants causing methemoglobinemia are rare causes of neonatal cyanosis. Hb F-Circleville is only the third fetal M-Hb reported to date. The prognosis of cyanosis is excellent in these cases, as Hb F declines post natally and is replaced by normal Hb A. Supplemental O2 may be required for several months during the postnatal period as was the case with this patient. Some fetal M-Hbs have been shown to arise as de novo mutations. In our case, an older sister and the mother were both proven to carry the Gγ63 His→Leu mutation consistent with autosomal dominant inheritance.

Aspekty diagnostyczne i terapeutyczne zespołu Marfana w wieku rozwojowym

2018 ◽  
Vol 22 (2) ◽  
Author(s):  
Małgorzata Ludzia ◽  
Ewa Smereczyńska-Wierzbicka ◽  
Bożena Werner
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Matrix Protein ◽  
Autosomal Dominant ◽  
De Novo ◽  
Enzyme Inhibitor ◽  
Angiotensin Receptor Blockers ◽  
Extracellular Matrix Protein ◽  
Long Bone ◽  
De Novo Mutations

Marfan’s syndrome (MFS) is a systemic, autosomal dominant connective tissue disease. It is caused mainly by the mutations in the FBN1 gene and is connected with extracellular matrix protein fibrillin-1. The incidence is about 2-3 per 10 000. About 70-75% of cases are inherited in an autosomal dominant fashion and the remaining are de-novo mutations. The most common findings involve cardiovascular, ocular and skeletal systems. The cardinal manifestations typically involving MFS are aortic root aneurysm/dissection and ectopia lentis. The other common manifestations are mitral valve prolapse, proximal aortic aneurysm, dolichocephaly, pectus carinatum deformity, enophthalmos, scoliosis, long-bone overgrowth. The manifestation in neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is a rapidly progressing multi-valvular cardiac disease. The death connected with congestive heart failure happens mainly within the first year of life. Prognostic factors for life expectancy of patients with Marfan syndrome depend on the type of the MFS and in classical MFS – depend on the rate of aortic root dilatation, which leads to dissection or rupture. Pharmacological management includes beta blockers, angiotensin receptor blockers and angiotensin converting enzyme inhibitor as a preventive treatment to slow aortic root dilation.

scholarly journals De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia

2016 ◽  
Vol 17 (3) ◽  
pp. 330-335 ◽  
Author(s):  
Yusuke Shimoda ◽  
Toshiya Osanai ◽  
Naoki Nakayama ◽  
Satoshi Ushikoshi ◽  
Masaaki Hokari ◽  
...  
Keyword(s):  
Family History ◽  
Arteriovenous Malformation ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
De Novo ◽  
The Family ◽  
Systemic Disorder ◽  
History Of ◽  
Cerebral Avms

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant systemic disorder characterized by the enlargement of capillaries, recurrent nosebleeds, and multiple arteriovenous malformations (AVMs). Although cerebral AVMs are traditionally considered to be congenital lesions, some reports have described de novo AVMs, which suggests that the authors believed them to be dynamic conditions. In this article, the authors describe the case of a 5-year-old boy with HHT in whom a de novo cerebral AVM was detected after a negative MRI result at 5 months. To the authors’ knowledge, this is the first report of a de novo AVM in a patient with HHT. In patients with a family history of HHT, de novo AVMs are possible, even when no lesions are detected at the first screening. Therefore, regular screenings need to be performed, and the family should be informed that AVMs could still develop despite normal MRI results.

scholarly journals Presence of De Novo Mutations in Autosomal Dominant Polycystic Kidney Disease Patients Without Family History

2008 ◽  
Vol 52 (6) ◽  
pp. 1042-1050 ◽  
Author(s):  
Berenice Reed ◽  
Kim McFann ◽  
William J. Kimberling ◽  
York Pei ◽  
Patricia A. Gabow ◽  
...  
Keyword(s):  
Family History ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
De Novo ◽  
De Novo Mutations ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

2015 ◽  
Vol 97 (3) ◽  
pp. 483-492 ◽  
Author(s):  
Björn Fischer-Zirnsak ◽  
Nathalie Escande-Beillard ◽  
Jaya Ganesh ◽  
Yu Xuan Tan ◽  
Mohammed Al Bughaili ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Cutis Laxa ◽  
De Novo Mutations

scholarly journals A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

2015 ◽  
Author(s):  
Jason O'Rawe ◽  
Yiyang Wu ◽  
Alan Rope ◽  
Laura T. Jimenez Barrón ◽  
Jeffrey Swensen ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Critical Role ◽  
False Negative ◽  
Disease Models ◽  
Sequencing Data ◽  
De Novo Mutations ◽  
Genetic Syndrome ◽  
Severe Intellectual Disability ◽  
The Family

We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nuclear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We derived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited missense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome.

scholarly journals Coding de novo mutations identified by WGS reveal novel orofacial cleft genes

2020 ◽  
Author(s):  
Madison R. Bishop ◽  
Kimberly Diaz Perez ◽  
Miranda Sun ◽  
Samantha Ho ◽  
Pankaj Chopra ◽  
...  
Keyword(s):  
Birth Defects ◽  
Autosomal Dominant ◽  
De Novo ◽  
Congenital Defects ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Significant Excess ◽  
Orofacial Clefts ◽  
Increase Risk ◽  
Human Birth

AbstractWhile de novo mutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

scholarly journals Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

2020 ◽  
Vol 9 (2) ◽  
pp. 370 ◽  
Author(s):  
Maria Franaszczyk ◽  
Grazyna Truszkowska ◽  
Przemyslaw Chmielewski ◽  
Malgorzata Rydzanicz ◽  
Joanna Kosinska ◽  
...  
Keyword(s):  
Candidate Genes ◽  
De Novo ◽  
Positive Family History ◽  
Disease Onset ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Whole Exome ◽  
The Family ◽  
High Prevalence ◽  
Generation Sequencing

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

Massive ribs fractures due to artriohepatic dysplasia (Alagille syndrome): a case report.

2018 ◽  
Author(s):  
Mohammed J Aboud
Keyword(s):  
De Novo ◽  
Alagille Syndrome ◽  
Pulmonary Artery Stenosis ◽  
De Novo Mutations ◽  
Stunted Growth ◽  
Notch Receptors ◽  
Chronic Cholestasis ◽  
The Family ◽  
Dominant Disease ◽  
History Of

Abstract   Alagille syndrome (ALGS) is a rare multisystem congenital disorder, with a minimum incidence of approximately 1:30,000 live births. It is an autosomal dominant disease that arises from mutations in the Jagged1 (JAG1) gene (approximately 60% of cases are caused by de novo mutations), which encodes a ligand for Notch receptors. The most common symptoms associated with this syndrome are cholestasis with the obstruction or slowing of biliary flow, congenital heart disease (pulmonary artery stenosis), and butterfly-shaped vertebrae, anterior chamber eye defects, and dysmorphic faces. Several of the characteristics of Alagille syndrome may result in patients having an especially high risk of fracture. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism. Case presentation; A 6-months-old girl admitted to pediatric surgery unit with jaundice since one month of age, progressive abdominal distention. She had been diagnosed with biliary atresia at the age of 1 month on the base of clinical diagnosis, she was malnourished with stunted growth. She had most of the features of Alagille syndrome. Chest radiographs showed generalized decreased in bone density with multiple ribs fractures on the left side, with pulmonary consolidation in the left middle and lower zone. Osteodystrophy (haptic cause) was enrolled based on the fact that there was no evidence or history of trauma (child abuse by the family was not considered). Our study is one of a few reports to document ribs fracture in children with AGLS. 

scholarly journals A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Rinki Ratnapriya ◽  
Samuel G. Jacobson ◽  
Artur V. Cideciyan ◽  
Milton A. English ◽  
Alejandro J. Roman ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Autosomal Dominant ◽  
De Novo ◽  
Causal Variant ◽  
Unaffected Individual ◽  
Retinal Degenerations ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
The Family ◽  
Major Progress

Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.

Obstructive hydrocephalus treated with endoscopic third ventriculostomy in a patient with Hajdu-Cheney syndrome: case report

2020 ◽  
Vol 26 (5) ◽  
pp. 513-516
Author(s):  
Ryan M. Johnson ◽  
Brent R. O’Neill
Keyword(s):  
Autosomal Dominant ◽  
Endoscopic Third Ventriculostomy ◽  
De Novo ◽  
Obstructive Hydrocephalus ◽  
Genetic Disorder ◽  
Aqueductal Stenosis ◽  
Third Ventriculostomy ◽  
De Novo Mutations ◽  
First Case ◽  
Complex Anatomy

Hajdu-Cheney syndrome (HCS) is a rare genetic disorder with autosomal dominant inheritance, although most cases result from de novo mutations. Progressive platybasia and basilar impression (BI) can potentiate obstructive hydrocephalus due to aqueductal stenosis. Limited literature exists on the surgical intervention for hydrocephalus in patients with this condition. The authors present (to their knowledge) the first case of obstructive hydrocephalus due to aqueductal stenosis from BI treated with an endoscopic third ventriculostomy in a patient with the complex anatomy of HCS.

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