scholarly journals Description of an ELANE Mutation in a Girl with Severe Congenital Neutropenia: A Paradigm of Targeted Genetic Screening Based on Clinical Findings

2018 ◽  
Vol 08 (01) ◽  
pp. 033-037
Author(s):  
Labrini Damianidou ◽  
Theodotis Papageorgiou ◽  
Athanasios Tragiannidis ◽  
Katerina Haidopoulou ◽  
Andreas Giannopoulos ◽  
...  
Keyword(s):  
Genetic Screening ◽  
Autosomal Dominant ◽  
Respiratory Infections ◽  
Clinical Findings ◽  
Diagnostic Strategy ◽  
Severe Congenital Neutropenia ◽  
Dominant Inheritance ◽  
Congenital Neutropenia ◽  
Exon 2 ◽  
Detailed Medical History

AbstractWe describe the case of a 5-year-old girl with severe congenital neutropenia presenting with recurrent skin and respiratory infections. Sequence analysis of ELANE and HAX1 genes identified a mutation in heterozygous state in exon 2 of the ELANE gene: c.157C > G (p.His53Asp), not previously described in the literature at the exon coding level. Given the autosomal dominant inheritance and the location of the mutation within a “hotspot,” this mutation was considered as clinically relevant. ELANE should be screened in patients with congenital neutropenia of no obvious etiology. A detailed medical history and clinical evaluation can prevent unnecessary investigations allowing for a targeted diagnostic strategy.

Unique Evidence for Autosomal Dominant Inheritance of Severe Congenital Neutropenia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1457-1457
Author(s):  
Laurence A. Boxer ◽  
Steven Stein ◽  
Danielle Buckley ◽  
Sandhya Subramanian ◽  
Audrey Anna Bolyard ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Autosomal Dominant ◽  
Autosomal Dominant Inheritance ◽  
Paternal Allele ◽  
Severe Congenital Neutropenia ◽  
Dominant Inheritance ◽  
Congenital Neutropenia ◽  
Sperm Donor ◽  
The Mean ◽  
Single Child

Abstract Severe congenital neutropenia was originally described as an autosomal recessive disorder characterized by severe neutropenia and recurrent bacterial infections from birth, but other reports indicate that autosomal dominant inheritance occurs. Several report now indicate that most, but not all, patients with severe congential neutropenia have heterozygous mutation in the gene for neutrophil elastase (NE or ELA2). We recently investigated an unusual series of cases of severe congenital neutropenia occurring when the same sperm donor was utilitized by four different families to impregnate mothers by either artificial insemination or in vitro fertilization. Three sets of twins were conceived and a single child in the four families. Collectively one set of twins and one child each from the other two families conceiving twins and the single child were all found to have severe congenital neutropenia. The mean for their median blood neutrophils (ANC) at diagnosis was 84 +/−32 x109/L (range 0–166 x 109 /L); and their other blood counts were remarkably similar. On treatment with G-CSF (mean dose 6.7+/− 1.3 SEM mcg/kg/day) the mean for the median ANC increased to 3290 +/−1410 x109/L( range 420–8600 x 109 /L ) To determine whether the sperm donor was responsible for transmitting severe congenital neutropenia, geonomic DNA from peripheral blood leukocytes was used to sequence the gene for neutrophil elastase in the affected children and their mothers using standard techniques. None of the mothers had a mutation in their NE gene but all five affected children had the same mutation effecting the fourth exon at site S97L. Since it was not possible to perform genetic analysis on biological samples from the donor, more detailed genetic linkage analysis was performed on the affected children and their mothers. Linkage mapping analysis of 22 microsatellite markers on chromosome 14 and 19 confirmed that all affected children possessed one of the two paternal alleles. For an 11 centiMorgan region immediately adjacent to the NE gene on chromosome 19, all affected children shared a single paternal allele, and 4 of 5 affected children shared a single paternal allele for a 20 centiMorgan region adjacent to the NE gene. The studies indicate that the father of the affected children provided consistent haplotypes that led to the expression of severe congenital neutropenia in all of the affected children. This investigation strongly implicates that autosomal dominant inheritance for severe congenital neutropenia. It also raises important questions for the evaluation of subjects in sperm donor programs.

Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2645-2650 ◽  
Author(s):  
Phil J. Ancliff ◽  
Rosemary E. Gale ◽  
Ri Liesner ◽  
Ian M. Hann ◽  
David C. Linch
Keyword(s):  
Neutrophil Elastase ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Autosomal Recessive Disorder ◽  
Severe Neutropenia ◽  
Base Substitution ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Gene Encoding ◽  
Familial Form

Abstract Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Subsequently, autosomal dominant and sporadic forms of the disease have been recognized. All forms are manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene encoding neutrophil elastase were detected in all families studied. Further work also demonstrated mutations in ELA2 in sporadic and autosomal dominant SCN. However, all mutations described to date are heterozygous and thus appear to act in a dominant fashion, which is inconsistent with an autosomal recessive disease. Therefore, the current study investigated whether mutations in ELA2could account for the disease phenotype in classical autosomal recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, though 1 was subsequently shown to be a low-frequency polymorphism. These results suggest that mutations in ELA2are not responsible for classical autosomal recessive Kostmann syndrome but provide further evidence for the role of ELA2 in SCN.

scholarly journals Genetic testing for familial exudative vitreoretinopathy

2017 ◽  
Vol 1 (s1) ◽  
pp. 51-53 ◽  
Author(s):  
Andi Abeshi ◽  
Carla Marinelli ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Leonardo Colombo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Slit Lamp ◽  
Dominant Inheritance ◽  
Familial Exudative Vitreoretinopathy

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for familial exudative vitreoretinopathy (FEVR). There is insufficient data to determine the prevalence of FEVR. Variations in the FZD4 (OMIM gene: 604579; OMIM disease: 133780), TSPAN12 (OMIM gene: 613138; OMIM disease: 613310) and ZNF408 (OMIM gene: 616454; OMIM disease: 616468) genes have autosomal dominant inheritance, whereas variations in LRP5 (OMIM gene: 603506; OMIM disease: 601813) have autosomal dominant or recessive inheritance and variations in NDP (OMIM gene: 300658; OMIM disease: 305390) have X-linked inheritance. Clinical diagnosis is based on clinical findings, family history, ophthalmological examination, fundoscopy, slit-lamp examination and fluorescein angiography. The genetic test is useful for confirming diagnosis and for differential diagnosis, couple risk assessment and access to clinical trials.

scholarly journals Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

2020 ◽  
Vol 146 (5) ◽  
pp. 1180-1193 ◽  
Author(s):  
Erika Van Nieuwenhove ◽  
John S. Barber ◽  
Julika Neumann ◽  
Elien Smeets ◽  
Mathijs Willemsen ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia

scholarly journals Genetic testing for Sorsby’s fundus dystrophy

2017 ◽  
Vol 1 (s1) ◽  
pp. 102-104
Author(s):  
Andi Abeshi ◽  
Carla Marinelli ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Lucia Ziccardi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Optical Coherence Tomography ◽  
Clinical Utility ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Dominant Inheritance ◽  
Sorsby's Fundus Dystrophy

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of the genetic test for Sorsby’s fundus dystrophy (SFD). SFD is caused by variations in the TIMP3 gene. Prevalence is, currently unknown. SFD has autosomal dominant inheritance. Clinical diagnosis is based on clinical findings, color vision testing, optical coherence tomography, ophthalmological examination and electroretinography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Predictors of Transformation to Myelodysplasia/Acute Myelogenous Leukemia (MDS/AML) in Severe Congenital Neutropenia (SCN).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3307-3307
Author(s):  
Laurence A. Boxer ◽  
Audrey Anna Bolyard ◽  
Peter E. Newburger ◽  
Mary Ann Bonilla ◽  
George Kannourakis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Alternative Therapy ◽  
Clinical Findings ◽  
Myelogenous Leukemia ◽  
Severe Congenital Neutropenia ◽  
Congenital Neutropenia ◽  
Increased Risk ◽  
Acute Myelogenous ◽  
History Of ◽  
Pre Treatment

Abstract Severe congenital neutropenia (SCN) is a heterogeneous disorder of myelopoiesis characterized by an absolute neutrophil count (ANC) persistently below 0.50 x 109/L (500/[um]L), with maturation arrest of neutrophil precursors of the bone marrow at the promyelocyte/myelocyte stage. G-CSF treated and untreated SCN patients are at risk of developing MDS/AML. Clinicians caring for these patients must vigilantly observe for evidence of evolution to malignancy and continually consider hematopoietic transplantation as an alternative therapy. We have previously reported that SCN patients requiring higher daily doses of G-CSF treatment (> 8 mcg/kg/day) are at an increased risk of MDS/AML, and that this risk is not predicted by pre-treatment bone marrow examinations or the pre-treatment ANC. We have reviewed clinical data for 46 patients over a 15-year period who were referred to the Severe Chronic Neutropenia International Registry (SCNIR) and developed MDS/AML. Four patients referred with a history of SCN had increased blasts on the bone marrow evaluation prior to G-CSF treatment or enrollment in the SCNIR. Blood counts were not available for two patients. For the other 40 patients, all treated with G-CSF for a median of 79 months (range 0.8 to 182 months), comparison of blood counts for the periods 12–24 months and 0–3 months before the diagnosis of MDS/AML showed: Changes in blood counts for the patient population may suggest a potential for malignant transformation. In these 40 cases, the principal clinical findings leading to the diagnosis of MDS/AML were: routine bone marrow surveillance 38%, decreased peripheral blood counts 26%, increased infections 10%, increased blasts in the blood 5%, decreased ANC with requirement for increased G-CSF dosage 2%, hepatosplenomegaly 2%, other (1 septal panniculitis and 1 leukemia cutis) 5%, and unknown 12%. The finding of mutations in the ELA2 gene in 10 of 15 cases (67%) did not influence the likelihood of MDS/AML. Previously we found that the duration and dose of G-CSF and alterations of the ANC on G-CSF therapy, suggest a high risk of transformation over time. Based on these data, the SCNIR recommends that patients with SCN have regular surveillance of blood counts every 1 to 2 months and annual bone marrow examinations with cytogenetic studies. Our findings suggest that a decline or change in blood counts of individual patients over a 3-month period may be informative in recognizing transformation to MDS/AML.

scholarly journals Genetic testing for Doyne honeycomb retinal dystrophy

2017 ◽  
Vol 1 (s1) ◽  
pp. 45-47
Author(s):  
Andi Abeshi ◽  
Pamela Coppola ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
Lucia Ziccardi ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Autosomal Dominant ◽  
Scientific Literature ◽  
Genetic Test ◽  
Retinal Dystrophy ◽  
Clinical Findings ◽  
Ophthalmological Examination ◽  
Dominant Inheritance ◽  
Doyne Honeycomb Retinal Dystrophy

Abstract We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Doyne honeycomb retinal dystrophy (DHRD). The disease has an autosomal dominant inheritance and is caused by variations in the EFEMP1 gene. There is insufficient data to establish the prevalence of DHRD. Clinical diagnosis is based on clinical findings, ophthalmological examination, electroretinography, fluorescein angiography and optical coherence tomography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

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