Vecchio D, Panfili FM, Macchiaiolo M
… +18 more, Dentici ML, Trivisano M, Medina CB, Capolino R, Salzano E, Cortellessa F, Busè M, Pantaleo A, Cocciadiferro D, Gonfiantini MV, Niceta M, De Dominicis A, Specchio N, Piccione M, Digilio MC, Tartaglia M, Novelli A, Bartuli A
Eur J Med Genet
· 2025 Feb · PMID 39709003
·
Publisher ↗
O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestat...O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.3 microdeletion encompassing the entire gene-locus. We further characterize both the clinical phenotype as well as its associated pathogenic variants' spectrum providing new information on sex-related phenotype distribution, according to the variant groups. We also highlight different epilepsy phenotype-genotype correlation with preferential association of generalized epilepsy and/or developmental and epileptic encephalopathy with missense pathogenic variants and focal epilepsy, childhood absence epilepsy and/or febrile seizures with pathogenic truncating variants and structural rearrangements. By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures.
Quinn S, Walsh N, Streata I
… +10 more, Ververi A, Kulshrestha S, Puri RD, Riza AL, Walsh A, Gorman K, Crushell E, Green A, Kenny J, Lynch SA
Eur J Med Genet
· 2025 Feb · PMID 39709002
·
Publisher ↗
BACKGROUND: The Roma population are an endogamous, genetically isolated, minority population who migrated from North-Western India to Europe from the 10th Century throughout the Byzantine period and continues to the pres...BACKGROUND: The Roma population are an endogamous, genetically isolated, minority population who migrated from North-Western India to Europe from the 10th Century throughout the Byzantine period and continues to the present day. Approximately 10-12 million Romani people reside in segregated settlements in Europe, and smaller populations live in North America and China. In addition to the endogamy, they also practice consanguinity. This has resulted in a higher frequency of rare autosomal recessive disorders some of which are unique to the Roma population. Some disorders result from founder variants whilst others are private variants, occurring within one nuclear family. Most are found as homozygous variants but compound heterozygosity is seen in a number of conditions. OBJECTIVE: Clinicians and scientists with experience in managing and diagnosing rare diseases in this population in Ireland, Romania and Greece have developed a comprehensive catalogue of autosomal recessive inherited disorders found in the Roma population. Our aim is that this catalogue will aid rapid diagnosis and highlight the differential diagnoses to consider in challenging cases. METHODS: We performed a detailed literature search to identify relevant publications and disease variants described in patients whose ethnicity was described as Roma. In addition, we interrogated data from local clinicians and colleagues in Ireland and Romania to collect additional unpublished variants which have yet to be reported in the medical literature. Where possible, we have mapped these disorders back to their European country of origin. Furthermore, we searched the variants allele frequencies on ClinVar. We analysed exome data from New Delhi, India to trace any of these founder variants back their origins. RESULTS: We identified 90 distinct autosomal recessive disorders, manifesting as 91 distinct phenotypes and 111 pathogenic disease variants. These include both published (n = 91) and unpublished (n = 20) findings identified in the Roma population in Europe. The Indian exome data revealed that only 12/111 variants were identified. CONCLUSION: We have assembled a catalogue of inherited autosomal recessive disorders and 111 pathogenic variants found in the Roma population. We hope that this will assist the medical and scientific community to make prompt diagnoses and consider adaptation of a targeted genetic approach to facilitate timely and cost-effective diagnoses in this population.
Laurent S, Vannier A, Gehrig C
… +4 more, Abramowicz M, Paoloni-Giacobino A, Cao Van H, Guipponi M
Eur J Med Genet
· 2025 Feb · PMID 39645194
·
Publisher ↗
Biallelic loss-of-function variants in STRC contribute to mild-moderate hearing loss (DFNB16). Here, we report a female patient with mild hearing loss. Exome sequencing and MLPA analysis revealed STRC biallelic inactivat...Biallelic loss-of-function variants in STRC contribute to mild-moderate hearing loss (DFNB16). Here, we report a female patient with mild hearing loss. Exome sequencing and MLPA analysis revealed STRC biallelic inactivation due to a nonsense and a CKMT1B-STRC deletion. Analysis of the self-reported normal-hearing parents revealed inconsistent Mendelian inheritance. Indeed, the mother was a heterozygous carrier of a CKTM1B-STRC-CATSPER2 deletion, and the father shared the same genotype as his daughter. He was later found to also have mild-moderate hearing loss. To address these discrepancies, we used long-read sequencing and optical genome mapping. We demonstrated that the father, in fact, carried a CKMT1B-STRC-CATSPER2 deletion in trans with the STRC nonsense variant and a tandem duplication of CATSPER2-CKMT1A. The proband inherited this latter haplotype, together with the maternal CKMT1B-STRC-CATSPER2 deletion. Combining these two technologies allowed us to fully elucidate the complex structural rearrangements at the STRC locus and provide appropriate genetic counselling.
Chatelain C, Kukor L, Bailleux S
… +3 more, Bours V, Bulk S, Docampo E
Eur J Med Genet
· 2025 Feb · PMID 39638120
·
Publisher ↗
Shprintzen-Goldberg syndrome is a rare systemic connective tissue disorder caused by heterozygous mutations in the Sloan-Kettering Institute (SKI) gene. The clinical presentation is reminiscent of Marfan and Loeys-Dietz...Shprintzen-Goldberg syndrome is a rare systemic connective tissue disorder caused by heterozygous mutations in the Sloan-Kettering Institute (SKI) gene. The clinical presentation is reminiscent of Marfan and Loeys-Dietz syndromes, making differential diagnosis challenging. Shprintzen-Goldberg syndrome's distinctive features are craniosynostosis and learning disabilities. The pathophysiology of these three conditions is similar as they all result in the deregulation of the transforming growth factor beta (TGF-β) signaling pathway and thus an altered expression of TGF-β responsive genes. We report a family of two patients: one with initial suspicion of hypermobile Ehlers-Danlos syndrome and the second with suspicion of Marfan syndrome, as the Marfan systemic score was positive and no craniosynostosis or learning disabilities were described. They were diagnosed with Shprintzen-Goldberg syndrome after a heterozygous probably pathogenic variant in the second mutational hotspot of SKI Dachshund homology domain was identified. We reviewed the genotype-phenotype correlation among the three mutational hotspots in SKI: the amino acids 20 to 35 of the receptor-regulated small mothers against decapentaplegic domain (group 1, n = 32), amino acids 94 to 117 of Dachshund homology domain (group 2, n = 12), and threonine 180 of Dachshund homology domain (group 3, n = 11 including our patients). As the main differential diagnoses of Shprintzen-Goldberg syndrome are Marfan and Loeys-Dietz syndromes, we completed the comparison already made by Loeys and Dietz. (2008) of Shprintzen-Goldberg syndrome clinical features among the different mutational hotspots with Marfan syndrome and the different types of Loeys-Dietz syndrome. In addition to the already described absence of learning disabilities in Shprintzen-Goldberg patients with a pathogenic variant in the threonine 180 of Dachshund homology domain, facial features also appeared to be less severe. The clinical overlap with Marfan and Loeys-Dietz patients requires genetic testing in order to establish an accurate molecular diagnosis at the variant level, and to adapt genetic counseling and clinical management.
Casellas À, Casellas-Grau A, Serra À
… +1 more, Busquets-Alibés E
Eur J Med Genet
· 2024 Dec · PMID 39603591
·
Publisher ↗
INTRODUCTION: Achondroplasia is a common skeletal dysplasia caused by a mutation in the FGFR3 gene, leading to disproportionate short stature and various clinical features. Despite the absence of definitive pharmacologic...INTRODUCTION: Achondroplasia is a common skeletal dysplasia caused by a mutation in the FGFR3 gene, leading to disproportionate short stature and various clinical features. Despite the absence of definitive pharmacological treatments, mindfulness-based interventions may offer psychosocial benefits for affected individuals and their families. OBJECTIVES: This study aimed to assess the feasibility and psychosocial effects of an online mindfulness intervention for children and adolescents with achondroplasia and their parents. METHODOLOGY: The intervention was an eight-week, synchronous online program with 15 participants: seven children and adolescents with achondroplasia and eight parents. Quantitative outcomes were assessed pre-and post-intervention using the State-Trait Anxiety Inventory for Children (STAIC) and the Multifactorial Self-Assessment Child Adaptation Test (TAMAI) for the younger participants, along with the Brief Symptom Inventory (BSI-18) for parents. Participant satisfaction was assessed using a customized survey, and qualitative data were collected through semi-structured interviews. RESULTS: The study demonstrated high feasibility, with 84.61% adherence and 93.75% participant satisfaction. Average anxiety levels decreased in children and adolescents (30.60 ± 5.12 to 26.80 ± 6.94, p = .285) and parents (3.67 ± 3.98 to 1.00 ± .89, p = .066). Emotional regulation was the most reported improvement category by children and adolescents (31.4%), while general well-being was the most noted by parents (29.63%). CONCLUSIONS: The results support the feasibility of this online mindfulness intervention for individuals with achondroplasia and their parents, indicating benefits for psychosocial well-being. Future studies should address these limitations by expanding sample sizes, exploring hybrid intervention models, and ensuring data anonymity. Integrating mindfulness into comprehensive psychosocial care strategies could enhance the quality of life for these populations.
Nakato D, Yasue Y, Matsubara K
… +7 more, Suzuki H, Kosaki R, Takenouchi T, Yamada M, Miya F, Takano-Shimizu T, Kosaki K
Eur J Med Genet
· 2024 Dec · PMID 39571789
·
Publisher ↗
Nonsense-mediated mRNA decay represents a biologic clearing system against aberrant mRNAs harboring nonsense and frameshift mutations and depends on three factors, UPF1, UPF2, and UPF3 (UPF3A, UPF3B). While germline path...Nonsense-mediated mRNA decay represents a biologic clearing system against aberrant mRNAs harboring nonsense and frameshift mutations and depends on three factors, UPF1, UPF2, and UPF3 (UPF3A, UPF3B). While germline pathogenic variants of UPF3B and UPF2 are known to be associated with neurodevelopmental disorders, germline variants in UPF1 have not been reported, until date, as being associated with any human disorders. Herein, we report two unrelated patients with de novo UPF1 variants. Patient 1 was a 5-year-old girl with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. Patient 2 was a 2-year-old female child with intellectual disabilities and similar features. Trio exome analysis revealed a de novo heterozygous variant in UPF1 in both the patients (Patient 1: NM_002911.4): c.949_951del, p.(Asp317del); Patient 2: c.1984G>A, p.(Asp662Asn)). We conducted experiments using Drosophila models to evaluate the functional relevance of these UPF1 variants. Enforced expression of the wild-type Upf1 allele under the control of the pan-neuronal nSyb-GAL4 driver caused mortality, mostly at the pupal stage, but still yielded adult flies. By contrast, expression of the Asp294del (Asp317del in humans) variant caused embryonic or early larval lethality and that of the Asp643Asn (Asp662Asn in humans) caused third instar larval lethality; neither produced pupa nor adult fly. Thus, the developmental defects caused by the variants, especially Asp294del, were more severe than those caused by the wild-type allele. These observations suggest that both variants are deleterious mutations. In conclusion, germline variants in UPF1 are associated with intellectual disabilities in humans.
Martín Gómez MA, Caba Molina M, León Fradejas M
… +2 more, Alonso Titos J, Del Pozo Alvarez R
Eur J Med Genet
· 2024 Dec · PMID 39490407
·
Publisher ↗
A 50-year-old woman presented with nephrotic proteinuria and preserved glomerular filtration rate. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and glomerular basement membrane thinning. Her brother ha...A 50-year-old woman presented with nephrotic proteinuria and preserved glomerular filtration rate. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) and glomerular basement membrane thinning. Her brother has a long history of chronic kidney disease, formerly diagnosed with minimal change disease, and eventually received a kidney allograft, developing high-grade proteinuria and decline in kidney function. FSGS was found by biopsy. Lastly, one paternal uncle suffered from the same condition, but he declined a biopsy. A genetic test identified a novel missense mutation in LMX1B, c.349G > A:p(Gly117Ser). Thus, the present series of cases shows a familial LMX1B-associated nephropathy presenting with FSGS.
Grosen A, Lautrup CK, Bahsen E
… +2 more, Jensen HK, Lildballe DL
Eur J Med Genet
· 2024 Dec · PMID 39481677
·
Publisher ↗
BACKGROUND: Genetic findings influence clinical care of patients suspected of hereditary cardiac diseases. As additional knowledge arises over time, the classification of genetic variants may change. The labor cost assoc...BACKGROUND: Genetic findings influence clinical care of patients suspected of hereditary cardiac diseases. As additional knowledge arises over time, the classification of genetic variants may change. The labor cost associated with systematic manual reevaluation for reported variants is substantial. We applied an automated variant classifier for reevaluation of previous reported variants to assess how such tools may assist in manual reevaluation. METHODS: Historically (2010-2022), patients (N = 2987) suspected of inherited cardiomyopathies or ion-channel disorders were screened for genetic variants in at least one of up to 114 genes. We had reported 1455 unique variants, of which 742 were among the 14 most relevant genes. In the 14-gene-group, we compared our reported classification to that of an autoclassifier and manually reevaluated variant classification of all variants. Among the remaining genes (N = 100), only variants where the autoclassifier predicted change of clinical impact, such as variant of uncertain significance to likely pathogenic or oppositely, were manually reevaluated. RESULTS: We identified 9% (66/742) of variants with clinical impact in the 14-gene-group. Of these, 91% could have been identified solely evaluating the 120 variants where the autoclassifier had predicted a change of clinical impact. In the 100 remaining genes, a change of clinical impact was identified in 3% (22/713) after manual reevaluation. CONCLUSION: Using an autoclassifier reduces the workload to identify variants likely to have a change in variant class with clinical impact. Hence, we recommend using such tools to identify the variants most relevant to manually reevaluate to improve patient care.
Graversen L, Sommerlund M, Kruse C
… +4 more, Gjørup H, Gregersen PA, Jensen UB, Blechingberg J
Eur J Med Genet
· 2024 Dec · PMID 39476951
·
Publisher ↗
Hypohidrotic Ectodermal Dysplasia is a syndrome with hypotrichosis, hypohidrosis, and hypodontia as the main symptoms. The prevalence is estimated to one in 5000-10,000 persons. In 10-15% the disease is caused by pathoge...Hypohidrotic Ectodermal Dysplasia is a syndrome with hypotrichosis, hypohidrosis, and hypodontia as the main symptoms. The prevalence is estimated to one in 5000-10,000 persons. In 10-15% the disease is caused by pathogenic variants in EDAR, and most of the known causal variants to date are missense or nonsense variants. We present a patient with classic Hypohidrotic Ectodermal Dysplasia and mammary gland aplasia with a duplication within EDAR as the likely cause. The duplication is de novo in the patient, and genome sequencing of DNA extracted from blood has revealed that the duplication is in tandem conformation, most likely entailing an altered EDAR protein with a dominant negative effect. This is to our knowledge the first report of an intragenic duplication in EDAR as causal for Hypohidrotic Ectodermal Dysplasia.
Arioka M, Nakamura S, Nishioka K
… +11 more, Inoue K, Nakao Y, Miyai Y, Morita H, Koyano K, Takenouchi T, Yasuda S, Chiba Y, Iwase T, Ueno M, Kusaka T
Eur J Med Genet
· 2024 Dec · PMID 39423952
·
Publisher ↗
Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and for...Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a de novo frameshift variant in ASXL1. Autopsy revealed that the lung was at the saccular stage, equivalent to 28-34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in ASXL1.
Barcia G, Scorrano G, Rio M
… +8 more, Gitiaux C, Hully M, Poirier K, Besmond C, Munnich A, Boddaert N, Chemaly N, Nabbout R
Eur J Med Genet
· 2024 Dec · PMID 39423951
·
Publisher ↗
Biallelic pathogenic variants in CNTNAP2, a gene encoding the contactin-associated protein-like 2, have been reported in patients with various clinical presentations including intellectual disability (ID), autistic spect...Biallelic pathogenic variants in CNTNAP2, a gene encoding the contactin-associated protein-like 2, have been reported in patients with various clinical presentations including intellectual disability (ID), autistic spectrum disorders (ASD), psychiatric disorders, and focal epilepsy rarely associated to focal cortical dysplasia. We report four children carrying novel biallelic CNTNAP2 pathogenic variants. They present global developmental delay, psychiatric disorders, and focal epilepsy. All patients displayed brain MRI abnormalities consistent with focal temporal dysplasia. One patient had a temporal resection before the availability of genetic testing. Focal cortical dysplasia represents a frequent finding related to focal refractory epilepsy in CNTNAP2 affected patients, and surgery seems to be ineffective in this setting. The genetic testing could therefore be impactful on treatment choices in refractory focal epilepsies.
Chen FH, Hartman AL, Letinturier MCV
… +16 more, Antoniadou V, Baynam G, Bloom L, Crimi M, Della Rocca MG, Didato G, Houge SD, Jonker A, Kawome M, Mueller F, O'Brien J, Puri RD, Ryan N, Thong MK, Tumienė B, Parisi MA
Eur J Med Genet
· 2024 Dec · PMID 39374775
·
Publisher ↗
The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs). The Task Force reviewed relat...The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs). The Task Force reviewed related literature published from January 2017 to August 2023, and identified various models and implementation strategies of TH for RD. The Task Force highlighted the reported value and benefits of using TH for RDs, along with the limitations and opportunities. The number of publications sharply increased since 2021, coinciding with the onset of the COVID-19 pandemic, which forced the rapid adoption of TH in many healthcare settings. One of the major benefits of TH for RDs lies in its capacity to surmount geographical barriers, which helps in overcoming the constraints posed by limited numbers and geographical dispersion of specialists. This was evident during the pandemic when TH was used to maintain a level of continued medical care and research when face-to-face visits were severely restricted. TH, through which clinical research can be decentralized, can also facilitate and enhance RD research by decreasing burden, expanding access, and enhancing efficiency. This will be especially beneficial when coupled with the adoption of digital health technologies, such as mobile health (mHealth) and wearable devices for remote monitoring (i.e., surveillance of outpatient data transmitted through devices), along with big data solutions. TH has also been shown to be an effective means for RD education and peer mentoring, enabling local health care providers (HCPs) to care for RD patients, which indirectly ensures that RD patients get the expertise and multidisciplinary care they need. However, limitations and weaknesses associated with using TH for RD care and research were also identified, including the inability to perform physical examinations and build relationships with HCPs. Therefore, TH has been recommended as a complement to, rather than substitute for, face-to-face consultations. There is also a concern that TH may lead to an amplification of health disparities and inequities related to social determinants of health for those with RDs due to lack of access to TH technologies, inadequate digital literacy, and geographical, socio-cultural, and linguistic barriers. Finally, the Task Force also discussed evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education.
Jonker AH, Buckinx T, Pannese L
… +3 more, Klap P, Sahel JA, Dooms M
Eur J Med Genet
· 2024 Dec · PMID 39374774
·
Publisher ↗
The field of rare disease therapeutics has witnessed significant growth in recent years, highlighting the need for diverse therapeutic approaches to cater to the unique needs of individuals with rare diseases. Rare disea...The field of rare disease therapeutics has witnessed significant growth in recent years, highlighting the need for diverse therapeutic approaches to cater to the unique needs of individuals with rare diseases. Rare disease therapies encompass a broad spectrum of interventions, including orphan medicinal products, orphan medical devices, rehabilitative therapies, and digital therapeutics, with the lines between these categories blurring. This paper covers the session of the RE (ACT)-IRDiRC Conference 2023 and delves into the landscape of orphan medical device research and development, shedding light on the challenges and opportunities in this burgeoning field. It provides a short overview of the different international legislations in the field. In addition, it highlights several exemplary orphan medical devices. The first example is an exoskeleton for boys with Duchenne Muscular Dystrophy, enabling them to maintain arm functionality and independence. Another example presented was an EEG device linked to an app detecting seizures in rare epilepsy conditions, which alerts caregivers to seizures in real-time but also facilitates objective seizure reporting for clinicians, aiding in diagnosis and treatment optimization. It also showcases the role of gamification and enabling technologies in addressing rare diseases, by showing a game designed for children with cystic fibrosis, and a telemedicine system for rehabilitation therapy. Both solutions aim to improve patients' understanding of their conditions and enhance their self-management. In conclusion, this paper underscores the critical need for patient-centric orphan and pediatric medical devices to provide therapeutic options for individuals with rare diseases. It highlights the impact of existing devices on enhancing the quality of life for rare disease patients and emphasizes the necessity for greater incentives and support for research and development in this field.
Khodzhaev K, Sudutan T, Erbilgin Y
… +5 more, Saritas M, Yegen G, Bozkurt C, Sayitoglu M, Kebudi R
Eur J Med Genet
· 2024 Dec · PMID 39322061
·
Publisher ↗
Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in...Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-κB pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL. The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G>A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased PXR expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells. Patients with homozygous PXR variant showed significantly high expression compared to PXR wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). PXR homozygous HRS cells had significantly higher PXR expression compared to PXR wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous PXR HRS cells showed increased PXR expression in nucleus (p < 0.001). PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous PXR HL cases. This study provided clinical evidence to previously reported Sxr mice model that develop multifocal lymphomas, had an aberrantly increased NF-κB expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis.
Aliyeva L, Beken S, Mancilar H
… +4 more, Albayrak E, Korkmaz A, Tander B, Alanay Y
Eur J Med Genet
· 2024 Dec · PMID 39322060
·
Publisher ↗
Pyloric atresia is a rare gastrointestinal anomaly with an incidence of 1/100,000 in live births. It is usually seen as an isolated condition or in combination with other congenital or hereditary anomalies. Autosomal rec...Pyloric atresia is a rare gastrointestinal anomaly with an incidence of 1/100,000 in live births. It is usually seen as an isolated condition or in combination with other congenital or hereditary anomalies. Autosomal recessive inherited either fatal or non-fatal variants of pyloric atresia with epidermolysis bullosa are known due to mutations in ITGA6, ITGB4, and PLEC genes. ITGB4 gene mutation was recently identified in 5 siblings in 2 families associated with familial isolated pyloric atresia. Herein, we present two siblings who had pyloric atresia together with a homozygous variant in the ITGB4 gene and without epidermolysis bullosa. The development of isolated familial pyloric atresia without epidermolysis bullosa may occur due to homozygous variants of the ITGB4 gene. Detection of more variants in this gene may help to establish a genotype-phenotype correlation and may suggest the ITGB4 gene in patients who have pyloric atresia without epidermolysis bullosa.
Zdolšek Draksler T, Bouman A, Guček A
… +4 more, Novak E, Burger P, Colin F, Kleefstra T
Eur J Med Genet
· 2024 Dec · PMID 39299514
·
Publisher ↗
Kleefstra syndrome (KLEFS1) is a rare genetic neurodevelopmental disorder affecting multiple body systems. It continues to be under-researched, and its prevalence remains unknown. This paper builds on the international K...Kleefstra syndrome (KLEFS1) is a rare genetic neurodevelopmental disorder affecting multiple body systems. It continues to be under-researched, and its prevalence remains unknown. This paper builds on the international KLEFS1 cohort of 172 individuals based on the caregiver-reported outcomes collected within the online data collection platform GenIDA and reports the occurrence, frequency and severity of symptoms in KLEFS1. The study clearly shows the importance of caregiver-reported outcomes collections in the rare disease domain. Moreover, the study emphasizes the need for more specific and enhanced data collection methods, suggesting recommendations to optimize caregiver-reported registries and foster an even more profound understanding of rare diseases.
Cho TJ, Lee H, Ko JM
… +4 more, Song M, Shin CH, Song HR, Kim OH
Eur J Med Genet
· 2024 Dec · PMID 39293509
·
Publisher ↗
Heterozygous variants of MATN3 is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in MATN3 (p.Arg121...Heterozygous variants of MATN3 is one of the common causes of multiple epiphyseal dysplasia (MED). Here we report three individuals from two unrelated families who harbor compound heterozygous variants in MATN3 (p.Arg121Trp and p.Val220Ala). Contrary to the MED phenotype, these individuals exhibit spondyloepimetaphyseal dysplasia (SEMD) resembling the phenotypes caused by homozygous MATN3 variants. Clinical manifestations included short stature, aggravating genu varum, joint laxity, and spinal abnormalities. Radiographic findings were distinct from typical MED. These compound heterozygous variants in the von Willebrand factor A domain of MATN3 expand the phenotypic spectrum associated with MATN3, and suggest that extreme MATN3 dysfunction resulting from dual variants can lead to a specific pattern of SEMD.
Iman A, Majaliwa E, Kambainei LG
… +3 more, Mremi A, Mensenkamp AR, Hamel BC
Eur J Med Genet
· 2024 Dec · PMID 39293508
·
Publisher ↗
Wilms tumor is the most common childhood renal malignancy. Though mostly non-genetic, it can be syndromic with the involvement of many Wilms tumor predisposing genes and non-syndromic with the involvement of four genes:...Wilms tumor is the most common childhood renal malignancy. Though mostly non-genetic, it can be syndromic with the involvement of many Wilms tumor predisposing genes and non-syndromic with the involvement of four genes: WT1, REST, TRIM28, and CTR9. Familial and bilateral Wilms tumors do occur, but these are rare. So far, four Wilms tumor families with pathogenic variants in the CTR9 gene have been described, all (presumably) inherited from unaffected fathers, and three leading to deletion of exon 9. We are reporting female siblings, of whom one has a bilateral Wilms tumor, with a novel pathogenic splice site variant in the CTR9 gene, leading to deletion of exon 9, and inherited from their asymptomatic father. The loss of heterozygosity in the tumor was confirmed. In conclusion, CTR9 pathogenic variants are a very rare cause of Wilms tumors and typically result in familial Wilms tumors.
Xi Q, Patel R, Linton-Willoughby T
… +4 more, Short J, Tischkowitz M, Snape K, Morris S
Eur J Med Genet
· 2024 Dec · PMID 39260602
·
Publisher ↗
BACKGROUND: The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis...BACKGROUND: The South West Thames Centre for Genomics implemented a wider diagnostic Next Generation Sequencing (NGS) gene panel for eligible cancer patients undergoing diagnostic testing whilst restricting data analysis and reporting for BRCA1/BRCA2/PALB2/CHEK2 1100delC only as per contemporaneous guidelines. This study investigated the cost-utility of reanalyzing existing diagnostic grade extended panel data for truncating germline pathogenic variants (GPVs) in known moderate risk cancer susceptibility genes (CSGs) and performing follow-up genetic testing for first-degree relatives if patients have an identified CSG allele. METHODS: Reanalysis of existing NGS data was undertaken in 889 samples from cancer patients contemporaneously eligible through the NHS England National Genomic Test Directory (NGTD) codes R207 (ovarian) or R208 (breast) who had tested negative for BRCA1/BRCA2/PALB2 and CHEK2 1100delC founder variant. We modeled the cost and health outcomes for comparisons between: 1. Extending reanalysis to ATM truncating GPVs (partial extended testing) versus historical genetic testing, and 2. Extending analysis to ATM truncating GPV/BRIP1 truncating GPV/CHEK2 truncating GPV excluding CHEK2 1100delC/RAD51C truncating GPV/RAD51D truncating GPV (full extended testing) versus historical genetic testing. RESULTS: For partial extended testing, the ICER compared with historical genetic testing was UK£49,671/QALY. For full extended testing, the ICER compared with historical genetic testing of historical genetic testing was UK£5716/QALY. The full extended testing remained cost-effective with a 30% increase in genetic testing cost. CONCLUSION: Where existing NGS data for cancer susceptibility genes is stored to diagnostic standard in UK laboratories, this study suggests it is cost-effective to analyze, report and clinically manage patients and relatives by extended analysis to an 8-gene panel compared to the historical genetic testing.
Beyzaei Z, Goudarzi Z, Dehghani SM
… +5 more, Moravej H, Imanieh MH, Ataollahi M, Heidari M, Geramizadeh B
Eur J Med Genet
· 2024 Oct · PMID 39260601
·
Publisher ↗
Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, which results in a deficiency of...Hereditary Tyrosinemia Type 1 (HT1) is a genetic disorder characterized by an autosomal recessive inheritance pattern, caused by mutations in the fumarylacetoacetate hydrolase (FAH) gene, which results in a deficiency of fumarylacetoacetase. In our study, we identified a total of 15 mutations, including 12 newly discovered and 3 previously reported pathogenic mutations, in a cohort of 19 Iranian patients with the acute form of HT1. Out of the 12 novel variants identified, 11 were missense variants: p.Asp126His, p.Gln75Glu, p.Leu385Pro, p.Ser92Thr, p.Leu96Arg, p.Val167Glu, p.Ala94Asp, p.Gly353Trp, p.Ser164Pro, p.Glu86His and p.Ala163Pro. Additionally, there was one nonsense variant, p.Try244X, that had not been previously reported. Interestingly, the Arg237X variant was found to be particularly prevalent in this study. Notably, three exons, namely exons 9, 3, and 6, exhibited a higher frequency of mutations. All of the identified variants are presumed to result in loss of function, impacting the clinical signs, disease progression, increasing tyrosine level, and the specific location of the mutation. Our study has provided valuable insights into the mutation spectrum of variants associated with HT1 disease which is reported for the first time from Iran. This information can facilitate the development of targeted mutation screening protocols, focusing on the most prevalent mutations within specific regions or ethnic groups.