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Frontiers in Genetics 2024In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from...
INTRODUCTION
In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS.
METHODS
A survey ( = 159) and semi-structured interviews ( = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future.
RESULTS
Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions.
CONCLUSION
Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals.
PubMed: 38903755
DOI: 10.3389/fgene.2024.1401705 -
Cureus May 2024Alstrom syndrome is an autosomal recessive disease. It affects multiple systems, including cardiovascular, renal, endocrine, and eyes. Our patient is a 25-year-old...
Alstrom syndrome is an autosomal recessive disease. It affects multiple systems, including cardiovascular, renal, endocrine, and eyes. Our patient is a 25-year-old female who presented with elevated creatinine. Her past medical history was significant for hypothyroidism, polycystic ovarian syndrome, blindness, cataracts, hearing loss, and heart problems. She had genetic testing done that revealed that she was homozygous for the ALMS1 gene and was diagnosed with Alstrom syndrome. She was followed by nephrology in the clinic and had chronic kidney disease (CKD) stage V. The patient traveled to Italy and was lost to follow-up.
PubMed: 38883129
DOI: 10.7759/cureus.60334 -
Cureus May 2024Alström syndrome is a genetic disease that impacts numerous systems in the human body. The symptoms can vary and appear gradually. Childhood obesity, heart disease...
Alström syndrome is a genetic disease that impacts numerous systems in the human body. The symptoms can vary and appear gradually. Childhood obesity, heart disease (cardiomyopathy), abnormalities in vision, and hearing issues are the main symptoms of this disorder in children. Diabetes mellitus, hepatic issues, and renal dysfunction can all occur over time. Genetic alterations in the ALMS1 gene are the cause of Alström syndrome. It has an autosomal recessive inheritance pattern. We address the case of a Saudi woman in her 20s. She had been initially referred for type 2 diabetes, intellectual disability since early childhood, metabolic acidosis, and micrognathia; however, she also exhibited blindness, chronic kidney disease (CKD), and hearing loss, all of which are indicative of Alström syndrome. DNA testing showed that she has a homozygous pathogenic variant in the ALMS gene. Autosomal recessive Alström syndrome has been confirmed as a genetic diagnosis. No other clinically significant variations were found that are associated with the mentioned phenotype. By reporting this mutation, we hope to learn more about the genotypic range of the disease, particularly in the Saudi population. As each member of the family underwent genetic testing, we established a stringent follow-up schedule for our patient and her family.
PubMed: 38883102
DOI: 10.7759/cureus.60396 -
International Journal of Cardiology Aug 2024>40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five...
BACKGROUND
>40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five individuals then develop a later-onset cardiomyopathy but wide clinical variability is observed, even within the same family. The rationale for this study is to provide a comprehensive evaluation of the cardiovascular phenotype in adults with AS.
METHODS
Adults attending the National Centre for AS in England were studied. All patients underwent biochemical, 12- lead electrocardiography, echocardiography, and cardiovascular magnetic resonance imaging.
RESULTS
47 adults with AS (64% male; mean age 33 years; 66% white British) were studied. Seven (15%) survived infantile cardiomyopathy and 23 (49%) developed adult-onset cardiomyopathy. Conventional risk factors for cardiovascular disease were present in 39 (83%). Abnormalities were present on biomarkers in 16 (34%), ECG 30 (64%), echocardiography 19 (40%) and CMR 31 (66%). Coronary artery imaging was performed in six (13%), with abnormalities in two. Cardiac, renal, and liver markers were more often impaired in older patients, with impaired left ventricular ejection fraction, reduced global longitudinal strain and late enhancement. 6 (13%) had severe pulmonary hypertension (mean pulmonary artery pressure 46 mmHg) due to left heart disease on invasive testing.
CONCLUSION
Cardiomyopathy is common in adults with AS, complicated in a significant proportion by atherosclerotic coronary artery disease and restrictive cardiomyopathy, confirmed on CMR and invasive testing. With advancing age, cardiovascular complications are compounded by contemporaneous renal and liver disease.
Topics: Humans; Male; Female; Adult; Phenotype; Alstrom Syndrome; Middle Aged; Young Adult; Adolescent; Electrocardiography; Echocardiography; Cardiomyopathies
PubMed: 38806112
DOI: 10.1016/j.ijcard.2024.132212 -
Yonago Acta Medica May 2024Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety... (Review)
Review
Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety of clinical manifestations, including progressive visual and hearing impairment, type 2 diabetes mellitus, dilated cardiomyopathy, and hepatic and renal dysfunction, in addition to obesity. Recent insights underline the pivotal involvement of the disease-associated gene () in cilia formation and function, leading to the classification of its clinical manifestations as a ciliopathy. This review delineates the diverse clinical indicators defining the syndrome and elucidates its pathological underpinnings.
PubMed: 38803594
DOI: 10.33160/yam.2024.05.010 -
Disease Models & Mechanisms May 2024Alström Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. These are...
Alström Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. These are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and are poorly understood. We assessed cardiac function of Alms1 knockout mice by echocardiography. Cardiac function was unaltered in global Alms1 knockout mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female, but not male knockout mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global knockout mice. Female mice with Pdgfrα-Cre-driven Alms1 deletion in cardiac fibroblasts and a small proportion of cardiomyocytes did not recapitulate the phenotype of global knockout at 23 weeks. In conclusion, adult female, but not male, Alms1-deficient mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear, but may involve metabolic or endocrine differences between sexes.
PubMed: 38756069
DOI: 10.1242/dmm.050561 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... May 2024To explore the genetic etiology for a patient with Alström syndrome (ALMS) presenting as dilated cardiomyopathy.
OBJECTIVE
To explore the genetic etiology for a patient with Alström syndrome (ALMS) presenting as dilated cardiomyopathy.
METHODS
A 41-year-old male patient who had presented at the Sixth Medical Center of PLA General Hospital on October 20, 2021 was selected as the study subject. Clinical and laboratory examinations were carried out. Whole exome sequencing (WES) was employed for genetic testing, and candidate variants were validated by Sanger sequencing and pathogenicity analysis.
RESULTS
The patient had a 14-year medical history characterized by dilated cardiomyopathy, complete atrioventricular block, visual impairment, sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes, hypertension, renal dysfunction, and paranoid delusions. Genetic testing revealed that he has harbored compound heterozygous variants of the ALMS1 gene, namely c.6823C>T (p.Arg2275Ter) and c.9442_9445dup (p.Ser3149LysfsTer2). Sanger sequencing confirmed that they were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1_VeryStrong+PM2_Supporting+PM3+PP3, PVS1_VeryStrong+PM2_Supporting+PM3). Literature review indicated that the complete atrioventricular block in the patient was a phenotype unreported previously.
CONCLUSION
The c.6823C>T (p.Arg2275Ter) and c.9442_9445dup (p.Ser3149LysfsTer2) compound heterozygous variants of the ALMS1 gene probably underlay the pathogenesis in this patient. Above findings have expanded the phenotypic spectrum of ALMS and provided insights for clinicians dealing with similar cases.
Topics: Humans; Male; Alstrom Syndrome; Adult; Cell Cycle Proteins; Genetic Testing; Exome Sequencing; Mutation; Asian People; East Asian People
PubMed: 38684308
DOI: 10.3760/cma.j.cn511374-20230401-00184 -
BMC Medical Genomics Apr 2024Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies,...
BACKGROUND
Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
METHODS
The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
RESULTS
A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
CONCLUSIONS
Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
Topics: Humans; Male; Female; Taiwan; Ciliopathies; Child; Child, Preschool; Mutation; Exome Sequencing; Bardet-Biedl Syndrome; Adolescent; Infant; Abnormalities, Multiple; Retina; Syndrome; Cilia; Eye Abnormalities; Cerebellum; Proteins; Kidney Diseases, Cystic
PubMed: 38671463
DOI: 10.1186/s12920-024-01880-0 -
Molecular Metabolism Jun 2024Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver....
OBJECTIVE
Alström Syndrome (AS), caused by biallelic ALMS1 mutations, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and fatty liver. Prior studies suggest that hyperphagia is accounted for by loss of ALMS1 function in hypothalamic neurones, whereas disproportionate metabolic complications may be due to impaired adipose tissue expandability. We tested this by comparing the metabolic effects of global and mesenchymal stem cell (MSC)-specific Alms1 knockout.
METHODS
Global Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfrα-Cre driver was used to abrogate Alms1 function selectively in MSCs and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfrα+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues.
RESULTS
Assessed on 45% fat diet to promote adipose expansion, global Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfrα-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfrα expression.
CONCLUSIONS
Mesenchymal deletion of Alms1 recapitulates metabolic features of AS, including fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. Hyperphagia in females may depend on Alms1 deficiency in oligodendrocyte precursor cells rather than neurones. AS should be regarded as a forme fruste of lipodystrophy.
Topics: Animals; Mice; Mice, Knockout; Male; Female; Mesenchymal Stem Cells; Alstrom Syndrome; Cell Cycle Proteins; Insulin Resistance; Fatty Liver; Obesity; Hyperphagia; Adipose Tissue; Mice, Inbred C57BL; Body Composition
PubMed: 38583571
DOI: 10.1016/j.molmet.2024.101933 -
Annals of Medicine and Surgery (2012) Apr 2024Alstrom syndrome is one of the rarest monogenic ciliopathy belonging to autosomal recessive disorder. The pathophysiology of Alstrom syndrome is not well understood but...
INTRODUCTION AND IMPORTANCE
Alstrom syndrome is one of the rarest monogenic ciliopathy belonging to autosomal recessive disorder. The pathophysiology of Alstrom syndrome is not well understood but based upon the available medical literature its mechanism can be linked with recessive mutation in Alstrom syndrome 1(ALSM1) gene resulting in various multiple organ involvement and poor prognosis. Moreover the co-occurrence of such syndrome simultaneously in twins in same period of time is considered rare.
CASE PRESENTATION
Monochorionic diamniotic twins male born to healthy parents with significant antenatal and natal history along with decreased vision in both eyes in both twins since neonatal period. Throughout the childhood the disease progressed without any confirmatory diagnosis during which the twins underwent simultaneous multiple systemic involvement such as legal blindness in both twins at the age of 11 years, insulin resistance and features of diabetes mellitus, sensorineural hearing loss, subclinical hypothyroidism and various deranged metabolic panels. Certain diagnosis of Alstrom syndrome was made at the age of 16 years in both twins after whole-exome sequencing.
CLINICAL DISCUSSION
Based on genetic profile alstrom syndrome is a unique diagnosis. Along with its multi-organ involvement features, its progression and prognosis should also be looked upon while diagnosis and management in such syndromic patients. The diagnostic delay in such cases is also a matter of concern which can result in further delay in halting adverse effects of the disease itself. The multidisciplinary approach with involvement of endocrionologist, ophthalmologist and audiologist can bring upon improvement in quality of life of the patients.
CONCLUSION
With the prevalence of 1 in million cases Alstrom Hallgren syndrome is one of the rare genetic disorder with poor prognosis. In our case we present classical findings in twins who were diagnosed as Alstrom syndrome concurrently and further diseases progressed simultaneously.
PubMed: 38576930
DOI: 10.1097/MS9.0000000000001796