Showing papers in "American Journal of Medical Genetics Part C-seminars in Medical Genetics in 2022"

Genotype–phenotype correlates in Joubert syndrome: A review

Abstract: Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the “molar tooth sign,” and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene‐phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene‐phenotype correlates in JS.

OFD1 : One gene, several disorders

Abstract: The OFD1 protein is necessary for the formation of primary cilia and left–right asymmetry establishment but additional functions have also been ascribed to this multitask protein. When mutated, this protein results in a variety of phenotypes ranging from multiorgan involvement, such as OFD type I (OFDI) and Joubert syndromes (JBS10), and Primary ciliary dyskinesia (PCD), to the engagement of single tissues such as in the case of retinitis pigmentosa (RP23). The inheritance pattern of these condition differs from X‐linked dominant male‐lethal (OFDI) to X‐linked recessive (JBS10, PCD, and RP23). Distinctive biological peculiarities of the protein, which can contribute to explain the extreme clinical variability and the genetic mechanisms underlying the different disorders are discussed. The extensive spectrum of clinical manifestations observed in OFD1‐mutated patients represents a paradigmatic example of the complexity of genetic diseases. The elucidation of the mechanisms underlying this complexity will expand our comprehension of inherited disorders and will improve the clinical management of patients.

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey

Abstract: In this Dispatch from Biotech, we briefly review the urgent need for extensive expansion of newborn screening (NBS) by genomic sequencing, and the reasons why early attempts had limited success. During the next decade transformative developments will continue in society and in the pharmaceutical, biotechnology, informatics, and medical sectors that enable prompt addition of genetic disorders to NBS by rapid whole genome sequencing (rWGS) upon introduction of new therapies that qualify them according to the Wilson and Jungner criteria (Wilson, J. M. G., & Jungner, G., World Health Organization. (1968). Principles and Practice of Screening for Disease. World Health Organization. Retrieved from https://apps.who.int/iris/handle/10665/37650). Herein we describe plans, progress, and clinical trial designs for BeginNGS (Newborn Genome Sequencing to end the diagnostic and therapeutic odyssey), a new international, pre‐competitive, public–private consortium that proposes to implement a self‐learning healthcare delivery system for screening all newborns for over 400 hundred genetic diseases, diagnostic confirmation, implementation of effective treatment, and acceleration of orphan drug development. We invite investigators and stakeholders worldwide to join the consortium in a prospective, multi‐center, international trial of the clinical utility and cost effectiveness of BeginNGS.

C3 glomerulopathy: Understanding an ultra‐rare complement‐mediated renal disease

Abstract: C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid‐phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end‐stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease‐specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti‐complement drugs are currently in clinical trials.

Newborn screening for neurodevelopmental diseases: Are we there yet?

Abstract: In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug‐based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Bardet–Biedl syndrome: The pleiotropic role of the chaperonin‐like BBS6, 10, and 12 proteins

Abstract: Bardet–Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin‐like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin‐like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.

Whole‐genome sequencing holds the key to the success of gene‐targeted therapies

Abstract: Rare genetic disorders affect as many as 3%–5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole‐genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first‐tier NBS technique at least for those disorders without appropriate high‐throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.

Newborn screening for Duchenne muscular dystrophy‐early detection and diagnostic algorithm for female carriers of Duchenne muscular dystrophy

Abstract: Duchenne muscular dystrophy (DMD) is the most common pediatric‐onset form of muscular dystrophy, occurring in 1 in 5,000 live male births. DMD is a multi‐system disease resulting in muscle weakness with progressive deterioration of skeletal, heart, and smooth muscle, and learning disabilities. Pathogenic/likely pathogenic (P/LP) variants in the DMD gene, which encodes dystrophin protein, cause dystrophinopathy. All males with a P/LP variant in the X‐linked DMD gene are expected to be affected. Two to 20% of female heterozygotes with a P/LP variant develop symptoms of dystrophinopathy ranging from mild muscle weakness to significant disability similar to Becker muscular dystrophy. Recently, with improvements in therapies and testing methodology, there is stronger evidence supporting newborn screening (NBS) for DMD for males and females because females may also develop symptoms. A consented pilot study to screen newborns for DMD was initiated in New York State (NYS) and conducted from 2019 to 2021. The identification of female carriers and the realization of the subsequent uncertainty of providers concerning follow‐up during the pilot led to the development of algorithms for screening and diagnosis of carrier females, including both NBS and cascade molecular testing of family members.

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Abstract: Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype‐driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision‐making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal‐perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype‐driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

Biallelic variants in TTC21B as a rare cause of early‐onset arterial hypertension and tubuloglomerular kidney disease

Abstract: Monogenic disorders of the kidney typically affect either the glomerular or tubulointerstitial compartment producing a distinct set of clinical phenotypes. Primary focal segmental glomerulosclerosis (FSGS), for instance, is characterized by glomerular scarring with proteinuria and hypertension while nephronophthisis (NPHP) is associated with interstitial fibrosis and tubular atrophy, salt wasting, and low‐ to normal blood pressure. For both diseases, an expanding number of non‐overlapping genes with roles in glomerular filtration or primary cilium homeostasis, respectively, have been identified. TTC21B, encoding IFT139, however has been associated with disorders of both the glomerular and tubulointerstitial compartment, and linked with defective podocyte cytoskeleton and ciliary transport, respectively. Starting from a case report of extreme early‐onset hypertension, proteinuria, and progressive kidney disease, as well as data from the Genomics England 100,000 Genomes Project, we illustrate here the difficulties in assigning this mixed phenotype to the correct genetic diagnosis. Careful literature review supports the notion that biallelic, often hypomorph, missense variants in TTC21B are commonly associated with early‐onset hypertension and histological features of both FSGS and NPHP. Increased clinical recognition of this mixed glomerular and tubulointerstitial disease with often mild or absent features of a typical ciliopathy as well as inclusion of TTC21B on gene panels for early‐onset arterial hypertension might shorten the diagnostic odyssey for patients affected by this rare tubuloglomerular kidney disease.

Georgia state spinal muscular atrophy newborn screening experience: Screening assay performance and early clinical outcomes

Abstract: The purpose of this study is to provide the results of the newborn screening (NBS) program for Spinal Muscular Atrophy (SMA) in the state of Georgia to determine disease incidence, time to diagnosis and treatment, and early outcomes. NBS for SMA was performed using real time PCR assays from February 2019 through February 2020 in a pilot phase of screening. This method continued as part of our official state panel, and here we describe the pilot period as well as the first year of standard screening through February 2021. Medical records of infants with a positive NBS were reviewed for time to confirmation and neurologic evaluation, SMN2 copy number, clinical information, and treatment. Descriptive statistics were applied. Of the 301,418 samples screened, there were 15 true positive (eight males) and 24 false positive cases. One patient was missed due to human error early in the pilot phase and presented after symptom onset. The incidence of SMA in Georgia is approximately 1 in 18,840 births per year. After the pilot phase, the false positive rate was found to be so low that all patients who test positive were immediately referred to neurology for further care. Four patients died prior to intervention. Ten patients received intervention. Gene therapy was the preferred treatment. One patient was lost to follow‐up; another was clinically followed. In conclusion, trends for treated patients show improved or stable motor function. Long‐term follow‐up will help determine the durability of treatment.

Clinical overview on RASopathies

Abstract: RASopathies comprise a group of clinically overlapping developmental disorders caused by genetic variations affecting components or modulators of the RAS‐MAPK signaling cascade, which lead to dysregulation of signal flow through this pathway. Noonan syndrome and the less frequent, clinically related disorders, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan syndrome‐like disorder with loose anagen hair are part of the RASopathy spectrum and share a recognizable pattern of multisystem involvement. This review describes the “Noonan syndrome‐like” phenotype as a common phenotypic signature of generalized developmental RAS pathway dysregulation. Distinctive features of the different entities are revisited against the background of the understanding of underlying genetic alterations and genotype correlations, which has evolved rapidly during the past 20 years, thereby leading to suggestions regarding the nosology of RASopathies.

Primary ciliary dyskinesia in Volendam: Diagnostic and phenotypic features in patients with a CCDC114 mutation

Abstract: Primary ciliary dyskinesia (PCD) is a heterogeneous disease, with impaired mucociliary clearance causing respiratory tract infections. A founding CCDC114 mutation has led to a relatively homogeneous and large Dutch PCD population in Volendam. Our aim was to describe their phenotype. Therefore, all Volendam PCD patients seen at the Amsterdam UMC were included in this study. Data were collected on lung function, microbiology, radiology, and ear‐nose‐throat (ENT) symptoms. A mixed effects model estimated lung function decline in %point per year (95% confidence interval [CI]). Thirty‐three (60%) out of approximately 56 Volendam PCD patients were treated at our center and included in this study. Only 30% of patients had situs inversus. FEV1 declined in children (−1.43%/year, CI: −1.80/−1.05), but not in adults (0.01%/year, CI: −0.36/0.38). Pseudomonas aeruginosa was cultured in 21% of children and 60% of adults, respectively. Patients who have been infected at some point with P. aeruginosa had a steeper decline in FEV1 as compared to patients that have never been infected. Neonatal symptoms (79%) and ENT problems (94%) were common; fertility issues however, were not (11%) common. Compared to other PCD cohorts, the Volendam/CCDC114 patients have a moderately severe phenotype with lung function decline predominantly occurring in childhood.

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C

Abstract: Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito‐urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%–20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Role of primary cilia and Hedgehog signaling in craniofacial features of Ellis–van Creveld syndrome

Abstract: Ellis–van Creveld syndrome (EvC) is an autosomal recessive genetic disorder involving pathogenic variants of EVC and EVC2 genes and classified as a ciliopathy. The syndrome is caused by mutations in the EVC gene on chromosome 4p16, and EVC2 gene, located close to the EVC gene, in a head‐to‐head configuration. Regardless of the affliction of EVC or EVC2, the clinical features of Ellis–van Creveld syndrome are similar. Both these genes are expressed in tissues such as, but not limited to, the heart, liver, skeletal muscle, and placenta, while the predominant expression in the craniofacial tissues is that of EVC2. Biallelic mutations of EVC and EVC2 affect Hedgehog signaling and thereby ciliary function, crucial factors in vertebrate development, culminating in the phenotypical features characteristic of EvC. The clinical features of Ellis–van Creveld syndrome are consistent with significant abnormalities in morphogenesis and differentiation of the affected tissues. The robust role of primary cilia in histodifferentiation and morphodifferentiation of oral, perioral, and craniofacial tissues is becoming more evident in the most recent literature. In this review, we give a summary of the mechanistic role of primary cilia in craniofacial development, taking Ellis–van Creveld syndrome as a representative example.

Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease

Abstract: Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high‐dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.

The role of cilia for hydrocephalus formation

Abstract: Hydrocephalus is a common finding in newborns. In most cases, it is caused by intraventricular hemorrhage associated with prematurity, whereas in some patients the cause of hydrocephalus can be traced back to genetic changes, associated with disease syndromes such as RASopathies, lysosomal storage diseases, dystroglycanopathies, craniosynostosis but also ciliopathies. Ciliopathies are a group of diseases that can affect multiple organ systems due to dysfunction or the absence of cilia. Cilia are small organelles, extending from the cell surface. Nonmotile monocilia are ubiquitously present during cell development fulfilling chemosensory functions, whereas specialized epithelia such as the ependyma, lining the inner surface of the brain ventricles, exhibit multiciliated cells propelling fluids along the cell surface. This review highlights ciliopathies and their pathophysiology in congenital hydrocephalus. While nonmotile ciliopathies are often associated with severe prenatal hydrocephalus combined with other severe congenital brain malformations, motile ciliopathies, especially those associated with defects in multiciliogenesis can cause hydrocephalus and chronic lung disease.

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Abstract: Enhanced signaling through RAS and the mitogen‐associated protein kinase (MAPK) cascade underlies the RASopathies, a family of clinically related disorders affecting development and growth. In RASopathies, increased RAS‐MAPK signaling can result from the upregulated activity of various RAS GTPases, enhanced function of proteins positively controlling RAS function or favoring the efficient transmission of RAS signaling to downstream transducers, functional upregulation of RAS effectors belonging to the MAPK cascade, or inefficient signaling switch‐off operated by feedback mechanisms acting at different levels. The massive effort in RASopathy gene discovery performed in the last 20 years has identified more than 20 genes implicated in these disorders. It has also facilitated the characterization of several molecular activating mechanisms that had remained unappreciated due to their minor impact in oncogenesis. Here, we provide an overview on the discoveries collected during the last 5 years that have delivered unexpected insights (e.g., Noonan syndrome as a recessive disease) and allowed to profile new RASopathies, novel disease genes and new molecular circuits contributing to the control of RAS‐MAPK signaling.

Review of genetic testing in kidney disease patients: Diagnostic yield of single nucleotide variants and copy number variations evaluated across and within kidney phenotype groups

Abstract: Genetic kidney disease comprises a diverse group of disorders. These can roughly be divided in the phenotype groups congenital anomalies of the kidney and urinary tract, ciliopathies, glomerulopathies, stone disorders, tubulointerstitial kidney disease, and tubulopathies. Many etiologies can lead to chronic kidney disease that can progress to end‐stage kidney disease. Despite each individual disease being rare, together these genetic disorders account for a large proportion of kidney disease cases. With the introduction of massively parallel sequencing, genetic testing has become more accessible, but a comprehensive analysis of the diagnostic yield is lacking. This review gives an overview of the diagnostic yield of genetic testing across and within the full range of kidney disease phenotypes through a systematic literature search that resulted in 115 included articles. Patient, test, and cohort characteristics that can influence the diagnostic yield are highlighted. Detection of copy number variations and their contribution to the diagnostic yield is described for all phenotype groups. Also, the impact of a genetic diagnosis for a patient and family members, which can be diagnostic, therapeutic, and prognostic, is shown through the included articles. This review will allow clinicians to estimate an a priori probability of finding a genetic cause for the kidney disease in their patients.

Duchenne expert physician perspectives on Duchenne newborn screening and early Duchenne care

Abstract: Duchenne muscular dystrophy (DMD) is a progressive, fatal neuromuscular disorder typically diagnosed between 4 and 5 years of age. DMD currently has five FDA approved therapies, which has led to increased interest in newborn screening (NBS) for DMD. Our objective was to explore the perspectives and predicted practices of physicians (primarily neurologists) who will likely be responsible for the follow‐up of infants identified with DMD through NBS. A short survey was developed and distributed to physicians who are responsible for providing care for patients with Duchenne at Certified Duchenne Care Centers across the USA. Twenty‐seven physicians responded to statements about benefit and readiness for dystrophinopathy NBS, which care recommendations they would make at initial infant visits, and when they would recommend initiating approved therapies. Most DMD physicians indicated they see benefit in NBS (82%) and believe the DMD care community is ready for NBS in dystrophinopathies (74%). The majority of physicians would recommend multiple interventions, including genetic counseling, maternal carrier testing, referral to early intervention services, screening siblings, discussion of clinical trials, exon skipping therapies, and assessment of social and language development at initial visits. The majority of physicians also indicated they would recommend initiating approved therapies much earlier than the typical age of diagnosis.

Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome

Abstract: Biallelic loss‐of‐function (LoF) variants in CENPF gene are responsible for Strømme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from −2.9 SDS to −5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted‐V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Strømme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case‐series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Strømme syndrome.

Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype

Abstract: Gene variants that dysregulate signaling through the RAS‐MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi‐system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype–phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11–16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1–24 months). Among 13/18 patients whose IESS resolved with anti‐seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre‐clinical models for severe epilepsy phenotypes.

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review

Abstract: Noonan, Costello, and cardio‐facio‐cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro‐intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome‐related disorders, Costello, and cardio‐facio‐cutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene. In cardio‐facio‐cutaneous syndrome feeding issues are usually present (90–100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required. Moreover, disorders associated with gastrointestinal dysmotility as gastro‐esophageal reflux and constipation are commonly reported in all the above‐mentioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

Genetic testing and glomerular hematuria—A nephrologist's perspective

Abstract: Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes—COL4A3, COL4A4, and COL4A5. Early diagnosis and pharmacologic intervention can delay the progression of chronic kidney disease and the onset of kidney failure in patients with Alport syndrome. This article describes the evolution of approaches to the diagnosis and early treatment of Alport syndrome.

Unlocking the potential of the UK 100,000 Genomes Project—lessons learned from analysis of the “Congenital Malformations caused by Ciliopathies” cohort

Abstract: We reviewed sequencing, variant and clinical data from patients recruited to the “ Congenital Malformations caused by Ciliopathies ” (CMC) cohort of the UK 100,000 Genomes Project (100K) (Best et al., 2021). 1 By using domain-specific knowledge of ciliopathy genetics (Reiter & Leroux, 2017; Wheway et al., 2019), and examining variants in non-ciliopathy disease genes, we were able to identify potentially causative variants beyond those reported by the triaging process implemented by Genomics England (GEL, the company set up to run 100K). As a result, we increased diagnoses from the 27/83 (32.5%) that were reported by GEL, to 43/83 (51.8%). During this work, we experienced several difficulties in accessing and working with the data and observed several limitations with the currently available datasets.

Scaling genetic resources: New paradigms for diagnosis and treatment of rare genetic disease

Abstract: Development of genetic tests for rare genetic diseases has traditionally focused on individual diseases. Similarly, development of new therapies occurred one disease at a time. With >10,000 rare genetic diseases, this approach is not feasible. Diagnosis of genetic disorders has already transcended old paradigms as whole exome and genome sequencing have allowed expedient interrogation of all relevant genes in a single test. The growth of newborn screening has allowed identification of diseases in presymptomatic babies. Similarly, the ability to develop therapies is rapidly expanding due to technologies that leverage platform technology that address multiple diseases. However, movement from the basic science laboratory to clinical trials is still hampered by a regulatory system rooted in traditional trial design, requiring a fresh assessment of safe ways to obtain approval for new drugs. Ultimately, the number of nucleic acid‐based therapies will challenge the ability of clinics focused on rare diseases to deliver them safely with appropriate evaluation and long‐term follow‐up. This manuscript summarizes discussions arising from a recent National Institutes of Health conference on nucleic acid therapy, with a focus on scaling technologies for diagnosis of rare disorders and provision of therapies across the age and disease spectrum.

Autosomal dominant tubulointerstitial kidney disease: A review

Abstract: The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD‐UMOD is also associated with hyperuricemia and gout. ADTKD‐REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD‐MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.

Systematic assessment of monogenic etiology in adult‐onset kidney stone formers undergoing urological intervention–evidence for genetic pretest probability

Abstract: Kidney stone disease (KSD) is a prevalent condition associated with high morbidity, frequent recurrence, and progression to chronic kidney disease (CKD). The etiology is multifactorial, depending on environmental and genetic factors. Although monogenic KSD is frequent in children, unbiased prevalence data of heritable forms in adults is scarce. Within 2 years of recruitment, all patients hospitalized for urological kidney stone intervention at our center were consecutively enrolled for targeted next generation sequencing (tNGS). Additionally, clinical and metabolic assessments were performed for genotype–phenotype analyses. The cohort comprised 155 (66%) males and 81 (34%) females, with a mean age at first stone of 47 years (4–86). The diagnostic yield of tNGS was 6.8% (16/236), with cystinuria (SLC3A1, SLC7A9), distal renal tubular acidosis (SLC4A1), and renal phosphate wasting (SLC34A1, SLC9A3R1) as underlying hereditary disorders. While metabolic syndrome traits were associated with late‐onset KSD, hereditary KSD was associated with increased disease severity in terms of early‐onset, frequent recurrence, mildly impaired kidney function, and common bilateral affection. By employing systematic genetic analysis to a less biased cohort of common adult kidney stone formers, we demonstrate its diagnostic value for establishing the underlying disorder in a distinct proportion. Factors determining pretest probability include age at first stone (<40 years), frequent recurrence, mild CKD, and bilateral KSD.

Newborn screening research sponsored by the NIH: From diagnostic paradigms to precision therapeutics

Abstract: Newborn screening (NBS) is a successful public health initiative that effectively identifies pre‐symptomatic neonates so that treatment can be initiated before the onset of irreversible morbidity and mortality. Legislation passed in 2008 has supported a system of state screening programs, educational resources, and an evidence‐based review process to add conditions to a recommended universal newborn screening panel (RUSP). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, has promoted NBS research to advance legislative goals by supporting research that will uncover fundamental mechanisms of disease, develop treatments for NBS disorders, and promote pilot studies to test implementation of new conditions. NICHD's partnerships with other federal agencies have contributed to activities that support nominations of new conditions to the RUSP. The NIH's Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) initiative funded research projects that considered how genomic sequencing could be integrated into NBS and its ethical ramifications. Recently, the workshop, “Gene Targeted Therapies: Early Diagnosis and Equitable Delivery,” has explored the possibility of expanding NBS to include genetic diagnosis and precision, gene‐based therapies. Although hurdles remain to realize such a vision, broad engagement of multiple stakeholders is essential to advance genomic medicine within NBS.

Special issue: Newborn screening research

Abstract: This Special Issue provides a wide-ranging update from the front lines of newborn screening (NBS) research and is the result of conversations and collaborations facilitated by the Newborn Screening Translational Research Network (NBSTRN) across the NBS community and their extended networks. For 14 years NBSTRN has accelerated research efforts to advance NBS by creating a research infrastructure available to the NBS community to discover novel technologies to screen, diagnose, and treat newborns.Authors in this Special issues share their innovative and impactful efforts to advance NBS to include additional conditions, populations, genomics, and information sharing.