scholarly journals Mosaicism and incomplete penetrance of PCDH19 mutations

2018 ◽  
Vol 56 (2) ◽  
pp. 81-88 ◽  
Author(s):  
Aijie Liu ◽  
Xiaoxu Yang ◽  
Xiaoling Yang ◽  
Qixi Wu ◽  
Jing Zhang ◽  
...  

BackgroundMutations in the PCDH19 gene have mainly been reported in female patients with epilepsy. To date, PCDH19 mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.ObjectiveWe aimed to investigate the occurrence of mosaic PCDH19 mutations in 42 families comprising at least one patient with PCDH19-related epilepsy.MethodsTwo male patients with mosaic PCDH19 variants were identified using targeted next-generation sequencing. Forty female patients with PCDH19 variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with PCDH19 variants.ResultsFive mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred PCDH19 variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.ConclusionOur study provides new insights into phenotype-genotype correlations in PCDH19 related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
E. Suljic ◽  
A. Kucukalic ◽  
N. Loncarevic ◽  
A. Bravo-Mehmedbasic

Introduction:Interictal depression as a co-morbid disorder can be seen among more than 40% of patients with epilepsy. Sex, epilepsy duration, type of seizures as well as applied antiepileptic drugs can cause development of depression which influence patient's life quality.Goal:To test relation between depressive disorders and patients sex, duration of illness, type of epileptic fits, antiepileptic therapy and life quality.Material and methods:Prospectively, randomly selected, we tested 300 patients with epilepsy, with or without depressive affective disorder at the Outpatient Department for Epilepsies at the Clinical Center Sarajevo. All patients answered Beck and Hamilton depression scale.Results:Baseline is consisded of male patients which made 54 % with the average age of 37.7 years, as well as female patients at average age 32.83 years. Depressive disorder according to the results at the Beck scale was present in 34%, and according to the Hamilton scale in 38.9%. Duration of illnesses longer than 20 years had 56% women with the expressed depressive disorder, compared to the 42% men's with depression (p< 0.01). Partial complex seizures were more often among women (p< 0.05). Carbamazepin as monotherapy was applied for more than a half of the baseline, and combined with carbamazepin significantly more frequently among men's (p< 0.0001), while female patients had significantly more often Lamotrigil.Conclusion:Depressive disorder is significantly more frequent among women with partial complex seizures, earlier epilepsy onset, and significantly more often on Phenobarbital therapy. Presence of depression with epilepsy significantly reduced patient's life quality.


Author(s):  
Toyoki Maeda ◽  
Takahiko Horiuchi ◽  
Naoki Makino

The telomere length and its distribution were compared between patients administered with and without hypnotics to see if regular administration of hypnotics is associated with their aging-related somatic telomere shortening. Male patients presented significant shortening of telomere length of circulating leukocytes in association with age (–41.9 bp/year, p = 0.045) in contrast with controls (–18.3 kb/year, p = 0.155). On the other hand, female patients presented no significant shortening of telomere length with aging (–16.4 bp/year, p = 0.372) in contrast with controls (–55.9 bp/year, p = 0.00005). These results suggested that regular administration of hypnotics is associated with aging progression in a gender-related manner. The administration of hypnotics could be an indicator as the somatic aging status and for the screening of background lifestyle-associated diseases promoting biological aging.


2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Kazutaka Nanba ◽  
Yuto Yamazaki ◽  
Nolan Bick ◽  
Kei Onodera ◽  
Yuta Tezuka ◽  
...  

Abstract Context Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among patients with aldosterone-producing adenoma (APA). For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare. Objectives To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach. Method Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing. Results CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including 2 previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs 60% (41/68); P &lt; 0.0001]. Conclusion IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients.


2021 ◽  
Vol 28 (3) ◽  
pp. 153-157
Author(s):  
Su Jin Kim ◽  
Ho Yun Lee ◽  
Tae Hyun Kim ◽  
Tae Hoon Kim ◽  
Kun Hee Lee

Background and Objectives: The alar-columellar relationship plays an important role in the esthetic balance of the nose. We analyzed alar rim deformities and aesthetic concerns and expectations among patients by deformity type in Korean primary rhinoplasty patients.Materials and Methods: Retrospective photographic analysis was done on 336 patients planning to undergo primary rhinoplasty at Kyung Hee University Hospital at Gangdong. We categorized their alar rim deformities as normal, hanging columella, retracted columella, hanging ala, retracted ala, convex ala, concave ala, thick ala, and a combination of the above. Patients’ aesthetic concerns and expectations about their nose were analyzed by preoperative questionnaire.Results: Of the enrolled patients, 38 (11.3%) had no alar rim deformities, and the other 298 patients (88.7%) had one or more deformities. The most prevalent alar rim deformity was hanging ala (59.2%), followed by convex ala (53.3%) and thick ala (32.1%). Male patients were more likely to have convex ala and retracted columella than female patients. More than one-half of the patients (64.1%) had two or more deformities and tended to be young (p=0.028). Patients with thick ala had several reasons for being dissatisfied with their nose and various demands for correction.Conclusion: Distinctive characteristics of alar rim deformities should be considered in surgical planning in order to obtain satisfactory results in Korean primary rhinoplasty patients.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3230-3230 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Patricia Ault ◽  
Gautam Borthakur ◽  
Elias Jabbour ◽  
...  

Abstract Dasatinib has been shown in non-clinical studies to cause fetal toxicities in animals, but the effect of exposure during conception and pregnancy in humans is not known. Despite the requirement for contraception while on therapy with dasatinib, occasional pregnancies have been reported. The current study and post-marketing data report the outcomes of pregnancies occurring among 16 patients (8 females and 8 males) who received dasatinib therapy. Among the 8 female patients found to be pregnant while on dasatinib therapy, induced abortion was reported in 3 cases: 2 due to patient decision and 1 for unknown reasons. Two cases of spontaneous abortion were reported. The first was at 8 weeks gestation in a 38-year-old patient (G1P1) with a history of tobacco use. Birth defects of the fetus were not reported; though it is unknown if an autopsy was performed. The other spontaneous abortion was reported at 9 weeks gestation in a 33-year-old patient (G3P3) taking dasatinib for over 2 years. The medical history of this patient includes tobacco and alcohol use. Of the 3 deliveries, one patient had a normal healthy infant. The second patient (age: 29 years, G2P2) delivered a healthy infant by Caesarean section at 7 months gestation (reason for Caesarean section unknown). This patient received dasatinib 140mg/day for approximately 4 months, but was ‘lost to follow up’ for 2 months and study drug compliance was unknown. Upon her return, the patient had a positive pregnancy test with an estimated gestation of 4 weeks. The infant was reported as ‘small for date’ but without obvious birth defects. Apgar scores were also unknown for this infant. In the final case, a patient on dasatinib 100mg/day for approximately 5 months was identified as pregnant (G0P0) at 21 weeks of gestation. The estimated delivery date has not yet occurred at the time of writing, but the pregnancy course has been normal. Among 8 male patients treated with dasatinib with partners becoming pregnant while on treatment, normal newborns were reported for 7 cases, with the outcome of the other case unknown. All male patients remained on treatment during and after the pregnancies. In 1 case, the mother experienced pre-eclampsia but delivered a healthy newborn at 37 weeks, without birth defects or neonatal complications. In summary, although the limited data reported in this study did not show evidence that dasatinib treatment has a negative impact on pregnancy (for the mother or fetus), patients receiving dasatinib should be advised to practice adequate contraception. Table 1. Outcome of Female Patients Electing to C regnancy Duration of Fetal Exposure to Dasatinib Fetal Outcome Maternal Outcome Dasatinib Dose* Duration of Dasatinib Therapy * at time of onset Pt D 5 weeks 8wk spontaneous abortion no adverse reaction reported 180 mg/day approximately 9.5 months Pt E 9 weeks 9wk spontaneous abortion no adverse reaction reported 100 mg BID 30 months Pt F 7 weeks normal healthy no adverse reaction reported 140 mg/day approximately 15 months Pt G unknown “small for date” – healthy newborn C-section at 7 months 140mg/day approximately 4 months Pt H 21 days to be determined 100mg/day 5 months


2020 ◽  
Vol 11 (4) ◽  
pp. 232-238 ◽  
Author(s):  
Masashi Ogasawara ◽  
Eiji Nakagawa ◽  
Eri Takeshita ◽  
Kohei Hamanaka ◽  
Satoko Miyatake ◽  
...  

The <i>NEXMIF</i> (<i>KIAA2022</i>) gene is located in the X chromosome, and hemizygous mutations in <i>NEXMIF</i> cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in <i>NEXMIF</i> also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with <i>NEXMIF</i> mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in <i>NEXMIF</i>. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with <i>NEXMIF</i> mutations.


2021 ◽  
Author(s):  
Yipeng Wang ◽  
Wei Wang ◽  
Chengrong Wang ◽  
Shanshan Li ◽  
Meng Zhang ◽  
...  

Abstract Background: Achondroplasia (ACH) is generally detected by abnormal prenatal ultrasound findings in the late stage of pregnancy and then confirmed by molecular genetic testing of fetal genomic DNA obtained invasively. Most ACH cases appear to be de novo mutations with FGFR3 gene, so it is a challenge to screen ACH fetus out in the early stage of pregnancy.Objective: The aim of this study was to validate the possibility of detect fetus ACH along with non-invasive prenatal screening(NIPS) routinely in the early stage of pregnancy.Methods: 5927 cases of pregnant women undergoing NIPS were enrolled in this study. An additional 5ml of blood was collected together with NIPS blood sampling. Cell free DNA was extracted for the detecting of fetus ACH. Droplet-digital PCR(ddPCR) method based on the amplification of the two possible mutant alleles (c. 1138G>A and c. 1138G>C) of FGFR3 gene was performed to screen fetus ACH. Prenatal ultrasound and amniocentesis were then performed to confirm the positive screening result of ACH cases. The mutation sites of fetus were identified via Sanger sequencing by using amniotic fluid cells. For the screen negative cases of pregnant women, we followed up the results of prenatal diagnosis or the general conditions of the newborns.Results: One pregnant woman with fetus ACH were screened out at 22 weeks by Non-invasive prenatal detecting. Later prenatal ultrasound confirmed fetal skeletal dysplasia. Sanger sequencing confirmed de novo FGFR3 1138G>A mutant of the fetus. No ACH fetus or newborns were found in the rest detected negative cases of enrolled pregnant women.Conclusion: ddPCR technology could effectively identify de novo mutation like ACH of fetus noninvasively. We prospect the clinical application of ddPCR can expand the range of prenatal screen in the future.


e-CliniC ◽  
2013 ◽  
Vol 1 (2) ◽  
Author(s):  
Ariesta Zubiah Ramadhini ◽  
L. S. Angliadi ◽  
Engeline Angliadi

Abstract: Stroke may cause a serious problem that leads to a disability or even mortality. The purpose is to determine such an incidence caused by hypertension at the Installation of Medical Rehabilitation RSUP Prof. dr. R. D. Kandou Manado based on the characteristic of age, gender and occupation. This research was taken at the Installation of Medical Rehabilitation RSUP Prof. R. D. Kandou Manado by using retrospective descriptive study method as well as examining 228 new cases of stroke patients that correlated with conclusion criteria. The result showed 8,3% patients at ≤44th years old, 33,3% patients at 45th – 54th years old, 32% patients at 55th – 64th years old, 20,25% patients at 65th – 74th years old, 6,1% patients at 75th – 84th years old. 53,1% male patients, 46,9% female patients. 33,3% retirement, 18% farmers, 18% government officers, 5,3% private employees, 2,2% drivers, 0,9% teachers and, 3,1% housewives. Keywords: incidence, hypertension, stroke   Abstrak: Stroke dapat menimbulkan masalah besar karena menyebabkan kecacatan dan kematian. Tujuan, mengetahui gambaran angka kejadian stroke akibat hipertensi di Instalasi Rehabilitasi Medik RSUP Prof. Dr. R. D. Kandou Manado sesuai dengan karakteristik umur, jenis kelamin, dan jenis pekerjaan. Penelitian dilakukan di Instalasi Rehabilitasi Medik BLU RSUP Prof. dr. R. D. Kandou Manado, dilakukan secara retrospektif deskriptif dan didapatkan sampel sebanyak 228 data pasien kunjungan baru kasus stroke sesuai kriteria inklusi yang ditetapkan. Hasil penelitian, pasien stroke berumur ≤44 tahun 8,3%, berumur 45 – 54 tahun 33,3%, berumur 55 – 64 tahun 32%, berumur 65 – 74 tahun 20,25%, berumur 75 – 84 tahun 6,1%. Pasien stroke berjenis kelamin laki – laki 53,1%, perempuan 46,9%. Pasien stroke yang berstatus pekerjaan pensiunan 33,3%, petani 18%, PNS 18%, pegawai swasta 5,3%, supir 2,2%, guru 0,9%, IRT 3,1%. Kata Kunci: gambaran angka kejadian, hipertensi, stroke


Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1128
Author(s):  
Marilena Nakaguma ◽  
Nathalia Garcia Bianchi Pereira Ferreira ◽  
Anna Flavia Figueredo Benedetti ◽  
Mariana Cotarelli Madi ◽  
Juliana Moreira Silva ◽  
...  

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.


2021 ◽  
Vol 9 (5) ◽  
pp. 232596712110064
Author(s):  
Matthew L. Vopat ◽  
Reed G. Coda ◽  
Nick E. Giusti ◽  
Jordan Baker ◽  
Armin Tarakemeh ◽  
...  

Background: The glenohumeral joint is one of the most frequently dislocated joints in the body, particularly in young, active adults. Purpose: To conduct a systematic review and meta-analysis to evaluate and compare outcomes between anterior versus posterior shoulder instability. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was performed using the PubMed, Cochrane Library, and MEDLINE databases (from inception to September 2019) according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were included if they were published in the English language, contained outcomes after anterior or posterior shoulder instability, had at least 1 year of follow-up, and included arthroscopic soft tissue labral repair of either anterior or posterior instability. Outcomes including return-to-sport (RTS) rate, postoperative instability rate, and pre- and postoperative American Shoulder and Elbow Surgeons (ASES) scores were recorded and analyzed. Results: Overall, 39 studies were included (2077 patients; 1716 male patients and 361 female patients). Patients with anterior instability had a mean age of 23.45 ± 5.40 years (range, 11-72 years), while patients with posterior instability had a mean age of 23.08 ± 8.41 years (range, 13-61 years). The percentage of male patients with anterior instability was significantly higher than that of female patients (odds ratio [OR], 1.36; 95% CI, 1.04-1.77; P = .021). Compared with patients with posterior instability, those with anterior instability were significantly more likely to RTS (OR, 2.31; 95% CI, 1.76-3.04; P < .001), and they were significantly more likely to have postoperative instability (OR, 1.53; 95% CI, 1.07-2.23; P = .018). Patients with anterior instability also had significantly higher ASES scores than those with posterior instability (difference in means, 6.74; 95% CI, 4.71-8.77; P < .001). There were no significant differences found in postoperative complications between the anterior group (11 complications; 1.8%) and the posterior group (3 complications; 1.6%) (OR, 1.12; 95% CI, 0.29-6.30; P = .999). Conclusion: Patients with anterior shoulder instability had higher RTS rates but were more likely to have postoperative instability compared with posterior instability patients. Overall, male patients were significantly more likely to have anterior shoulder instability, while female patients were significantly more likely to have posterior shoulder instability.


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