A 2-Year-Old Child with Bilateral Ectopis Lentis and a Novel FBN1 Gene Variant Cys129Ser

AbstractMarfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband.

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Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Genetics in Medicine ◽

10.1038/s41436-020-01078-6 ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Hélène Morel ◽

Olivier Milleron ◽

Laurent Gouya ◽

Christine Francannet ◽

...

Keyword(s):

Marfan Syndrome ◽

Somatic Mosaicism ◽

Variant Calling ◽

Copy Number Variations ◽

Pathogenic Variant ◽

Single Nucleotide Variants ◽

Bioinformatics Analyses ◽

Single Nucleotide ◽

Fbn1 Gene ◽

Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00160-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Kodai Abe ◽

Arisa Ueki ◽

Yusaku Urakawa ◽

Minoru Kitago ◽

Tomoko Yoshihama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Genetic Analysis ◽

Pathogenic Variant ◽

Familial Pancreatic Cancer ◽

Case Presentation ◽

Pathogenic Variants ◽

Pancreatic Cancers ◽

Epidemiological Surveys ◽

History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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A Case Report of Calcium-Sensing Receptor Gene Variant and Primary Hyperparathyroidism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.351 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A173-A174

Author(s):

Sabaa Salim Joad ◽

Mary Emily Fang ◽

Jennifer E Posey ◽

Ruchi Gaba

Keyword(s):

Family History ◽

Receptor Gene ◽

Pathogenic Variant ◽

Gene Variant ◽

Calcium Sensing Receptor ◽

Subtotal Parathyroidectomy ◽

Calcium Sensing ◽

Post Surgery ◽

History Of ◽

Calcium Sensing Receptor Gene

Abstract Introduction: Primary hyperparathyroidism (PHPT) is an endocrinopathy that results from excessive production of parathyroid hormone from one or more overactive parathyroid gland(s). An estimated 90% of PHPT cases are sporadic, and 10% are inherited, comprising familial hyperparathyroidism (FHP). In FHP syndromes, variable clinical features are partly attributed to genetic heterogeneity. While there is not a consensus whether Familial hypocalciuric hypercalcemia (FHH) is a distinct entity or a form of FHP, accurate diagnosis is critical in guiding proper decision-making. The utility of genetic testing is multi-fold: help inform most likely diagnosis, guide prognosis and management, and inform familial recurrence risk. We report a patient with early-onset hypercalcemia, post subtotal parathyroidectomy, notable family history, with a likely pathogenic variant in the calcium-sensing receptor gene, CASR. Case Presentation: A 42 yo, female with history of nephrolithiasis and hypercalcemia diagnosed in her 20’s with PHPT was referred to our endocrinology clinic. Preoperative work up showed calcium of 11.1mg/dL, albumin 4.2g/dL, PTH of 177pg/mL, creatinine 0.92mg/dL. Sestamibi showed persistent activity in the mid to inferior aspect of right thyroid lobe suspicious for parathyroid adenoma. She underwent 3 gland parathyroidectomy and pathology showed mildly hypercellular parathyroid in left superior & right superior gland, normocellular left inferior gland. PTH levels normalized post-surgery. PTH levels normalized post surgery. Genetic evaluation was done, given her early-onset hypercalcemia, multi-gland involvement, and notable family history (maternal grandfather with parathyroidectomy for hypercalcemia and mother reportedly undergoing a hyperparathyroidism workup). Invitae hyperparathyroidism genetic panel revealed a likely pathogenic variant in CASR (c.659G>A; p.R220Q). Discussion: To date, our case with PHPT is the second report of the likely pathogenic variant CASR (c.659G>A; p.R220Q), which affects a conserved extracellular domain residue, thought to be important in sensing extracellular calcium. This variant has been previously reported in another family with FHH with 5 affected relatives. The reported 29-year old proband also had recurrent pancreatitis, which resolved with subtotal parathyroidectomy, but remained hypercalcemic. Despite the marked phenotypic heterogeneity in our patient and the case with FHH in terms of clinical presentation and response to treatment with surgery; both shared a history of hyperparathyroidism and a family history of hypercalcemia, suggesting contributions from the same CASR gene variant. With limited existing data about the variable expressivity of variants in genes implicated in the pathogenesis of both FHH and FHP; our case adds value to the existing evidence that supports its possible genetic contribution to PHPT

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Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old

Disease Markers ◽

10.1155/2021/9981028 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yi Zhang ◽

Yizhuo Wang ◽

Dongsheng Huang ◽

Jianmin Ma ◽

Weiling Zhang ◽

...

Keyword(s):

Family History ◽

Clinical Phenotype ◽

Acid Sites ◽

Pathogenic Variant ◽

Rb1 Gene ◽

Genetic History ◽

High Risk Factors ◽

Pathogenic Variants ◽

History Of ◽

Hereditary Tumors

Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month ( P = 0.021 , 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

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Coffin-Lowry preprint 2018

10.31219/osf.io/6scqn ◽

2018 ◽

Author(s):

Paolo Moretti

Keyword(s):

Family History ◽

Clinical Features ◽

De Novo ◽

Severe Disease ◽

Immunosuppressive Treatment ◽

Pathogenic Variant ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

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P1247FLNC pathogenic variants in patients with various cardiomyopathies:prevalence and genotype-phenotype correlations

European Heart Journal ◽

10.1093/eurheartj/ehz748.0205 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

F Ader ◽

P De Groote ◽

P Reant ◽

D Dupin-Deguine ◽

C Rambaud ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Cardiac Death ◽

Left Ventricular ◽

Pathogenic Variant ◽

Pathogenic Variants ◽

History Of ◽

Custom Panel ◽

Few Data ◽

First Time

Abstract Background/Introduction Pathogenic variants FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes.However, few data on phenotype-genotype correlation are available. Purpose Our aim was to estimate the prevalence of FLNC pathogenic variants in cardiomyopathies and to study the relations between phenotype and genotype. Methods DNAs from a cohort of 1150 unrelated index-patients with an isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 52 cardiomyopathy disease-causing genes. Results A FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1 to 8% depending on the cardiomyopathy subtypes. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame variants were found in other phenotypes. This work reported for the first time a left ventricular non-compaction associated with FLNC pathogenic variant. In the cohort, nine patients (32%) were implanted with an automatic defibrillator. In 7 families (25%), history of sudden cardiac death (SCD) before 50 years was reported. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (p=0.01). Four patients died of cardiac cause including 3 from SCD and 1 from heart failure. Conclusion This work highlights the role of FLNC in cardiomyopathies. A correlation between the type of the variant and the cardiomyopathy subtype was observed as well as with SCD risk. These new data should be taken into consideration for patient's management and primary prevention of sudden cardiac death. Acknowledgement/Funding La ligue contre la Cardiomyopathie

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Intraocular Lens Subluxation in Marfan Syndrome

The Open Ophthalmology Journal ◽

10.2174/1874364101408010048 ◽

2014 ◽

Vol 8 (1) ◽

pp. 48-50 ◽

Cited By ~ 4

Author(s):

Bolaños-Jiménez Rodrigo ◽

López-Lizárraga E Paulina ◽

March de R Francesc ◽

Telich-Tarriba J Eduardo ◽

Navas Alejandro

Keyword(s):

Emergency Department ◽

Marfan Syndrome ◽

High Myopia ◽

Ectopia Lentis ◽

Lens Subluxation ◽

Tricuspid Insufficiency ◽

Risks And Benefits ◽

Body Sensation ◽

History Of

Purpose : Ectopia lentis (EL) is a major criteria for the diagnosis of Marfan syndrome, it may vary from an asymptomatic mild displacement to a significant subluxation that places the equator of the lens in the pupillary axis. The purpose of this work is to present the case of a patient with Marfan syndrome who received treatment for subluxation at our institution. Case Report : A 51-year-old female diagnosed with Marfan syndrome presented to the emergency department with bilateral eye redness, foreign body sensation and crusting around the eyes on awakening. She had the following history of cardiac and ophthalmologic complications, including: 1. Lens subluxation 2. High myopia 3. Aortic root dilation, 4. Mitral valve prolapse and 5. Tricuspid insufficiency. Conclusion : The ophthalmological management of Marfan patients is challenging and periodical follow-up is needed. Surgical versus conservative management is controversial, each case needs to be evaluated individually to analyze the risks and benefits of the procedures.

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Allelic Frequencies of FBN1 Gene Polymorphisms and Genetic Analysis of Italian Families with Marfan Syndrome

Human Heredity ◽

10.1159/000022910 ◽

2000 ◽

Vol 50 (3) ◽

pp. 175-179 ◽

Cited By ~ 1

Author(s):

Monica Mottes ◽

Stefania Mirandola ◽

Federica Rigatelli ◽

Francesca Zolezzi ◽

Veronica Lisi ◽

...

Keyword(s):

Genetic Analysis ◽

Marfan Syndrome ◽

Gene Polymorphisms ◽

Allelic Frequencies ◽

Fbn1 Gene

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Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser))

Diagnostics ◽

10.3390/diagnostics11061034 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1034

Author(s):

Gaetano Pietro Bulfamante ◽

Laura Carpenito ◽

Emma Bragantini ◽

Silvia Graziani ◽

Maria Bellizzi ◽

...

Keyword(s):

Sequence Analysis ◽

Clinical Manifestations ◽

Pathogenic Variant ◽

Arterial Calcification ◽

Medium Size ◽

Internal Elastic Lamina ◽

Pathogenic Variants ◽

Abcc6 Gene ◽

Enpp1 Gene

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

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Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals

Frontiers in Genetics ◽

10.3389/fgene.2020.590486 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katarína Fabišíková ◽

Olívia Hamidová ◽

Regína Lohajová Behulová ◽

Katarína Závodná ◽

Petra Priščáková ◽

...

Keyword(s):

Family History ◽

Molecular Analysis ◽

Excision Repair ◽

Dna Lesions ◽

Pathogenic Variant ◽

Sequencing Analysis ◽

Biallelic Mutation ◽

Pathogenic Variants ◽

Mutyh Gene ◽

History Of

MUTYH-associated polyposis (MAP) is a rare hereditary condition caused by the biallelic mutation in the MUTYH gene encoding MUTYH glycosylase. This enzyme is a key member of the base excision repair (BER) pathway responsible for the repair of DNA lesions formed by reactive oxygen species (ROS). We report two cases of MAP. In case 1, a 67-year-old woman who presented with a personal history of colorectal and endometrial cancer and a family history of cancer syndromes underwent multigene panel testing that revealed a germline homozygous (biallelic) pathogenic variant c.1187G > A (p.Gly396Asp) in the MUTYH gene. Subsequent sequencing analysis performed in the offspring of the proband identified all three asymptomatic offspring as carriers of this pathogenic variant. In case 2, a 40-year-old woman with a strong family history of colorectal cancer [the proband’s sister was a carrier of the pathogenic variant c.536A > G (p.Tyr179Cys) of the MUTYH gene] and renal cancer underwent sequencing analysis of the MUTYH gene. The pathogenic heterozygous (monoallelic) variant c.536A > G (p.Tyr179Cys) of the MUTYH gene was identified in the proband. We found another pathogenic variant of the MUTYH gene—heterozygous (monoallelic) mutation c.1187G > A (p.Gly396Asp) in the genome of the proband’s husband. Molecular analysis of their offspring revealed that they are compound heterozygotes for MUTYH pathogenic variants c.536A > G (p.Tyr179Cys)/c.1187G > A (p.Gly396Asp). This paper shows the importance of genetic testing of asymptomatic relatives of the proband to ensure an early surveillance and management of individuals positive for pathogenic variant (s) in the MUTYH gene.

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