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Objective To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and Methods Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. Results The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P Conclusion In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Lysosomal storage diseases (LSDs) are a heterogeneous group of conditions causing substrate accumulation leading to progressive organ damage. Newborn screening (NBS) for several LSDs has become available in recent years due to advances in technology and treatment availability. While early initiation of treatment is lifesaving for those with infantile presentations, controversy continues regarding diagnosis of milder, later-onset diseases in infancy, including creation of pre-symptomatic populations of 'patients-in-waiting', the potential for medicalization, stigmatization, and/or discrimination. In-depth interviews were conducted with 36 adults [11 with Fabry disease (FD), 8 with Gaucher disease (GD), and 17 with late-onset Pompe disease (LOPD)], to determine their perspectives on NBS for their respective conditions. Thirty-four of 36 participants were in favor of NBS; both participants not in favor had GD1. Emergent themes influencing participants favorably toward NBS included earlier age of onset, a long diagnostic odyssey, less efficacious treatment, and the desire to have made different life decisions (e.g., relationships, career, or lifestyle) with the knowledge of their diagnosis. Concerns about insurance discrimination and psychological or physical burdens were associated with less favorable opinions of NBS. The ability for parents to make future reproductive decisions based their child's NBS result was considered favorably by some participants and unfavorably by others. Participants' specific condition (GD1, FD, or LOPD) contributed to these experiences differently. Participants with LOPD and FD favored NBS to initiate earlier treatment and prevent irreversible organ damage, whereas fewer patients with GD1 mentioned this benefit. Participants with LOPD had the longest diagnostic odyssey, while those with FD were more likely to report feeling misunderstood and experiencing accusations of malingering, both contributing to favorable views of NBS. Results expand prior quantitative findings by illuminating how participants' lived experiences can shape opinions about NBS. By understanding how currently affected individuals perceive the lifelong impact of a NBS result, genetic counselors can provide better anticipatory guidance to the parents of individuals diagnosed with a later-onset LSD by NBS.

The addition of Pompe disease (PD) and other conditions with later-onset forms to newborn screening (NBS) in the United States (US) has been controversial. NBS technology cannot discern infantile-onset PD (IOPD) from later-onset PD (LOPD) without clinical follow-up. This study explores genetic health care practitioners' (HCPs) experiences and challenges providing NBS patient care throughout the US and their resultant opinions on NBS for PD. An online survey was distributed to genetic counselors, geneticists, NBS follow-up care coordinators, and nurse practitioners caring for patients with positive NBS results for PD. Analysis of 78 surveys revealed the majority of participating HCPs support inclusion of PD on NBS. Almost all HCPs (93.3%) feel their state has sufficient resources to provide follow-up medical care for IOPD; however, only three-fourths (74.6%) believed this for LOPD. Common barriers included time lag between NBS and confirmatory results, insurance difficulties for laboratory testing, and family difficulties in seeking medical care. HCPs more frequently encountered barriers providing care for LOPD than IOPD (53.9% LOPD identified ≥3 barriers, 31.1% IOPD). HCPs also believe creation of a population of presymptomatic individuals with LOPD creates a psychological burden on the family (87.3% agree/strongly agree), unnecessary medicalization of the child (63.5% agree/strongly agree), and parental hypervigilance (68.3% agree/strongly agree). Opinions were markedly divided on the use of reproductive benefit as a justification for NBS. Participants believe additional education for pediatricians and other specialists would be beneficial in providing care for patients with both IOPD and LOPD, in addition to the creation of evidence-based official guidelines for care and supportive resources for families with LOPD.

Objective To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing. Patients and Methods In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel–based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics. Results Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result=did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk). Conclusion Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.

Pompe disease (PD) is an autosomal recessive lysosomal storage disorder causing progressive glycogen accumulation in muscles, with variability in age of onset and severity. For infantile-onset PD (IOPD), initiation of early treatment can be life-saving; however, current newborn screening (NBS) technology cannot distinguish IOPD from late-onset PD (LOPD) without clinical workup. Therefore, families of LOPD infants diagnosed by NBS may now spend years or even decades aware of their illness before symptoms appear, creating a pre-symptomatic awareness phase with which the medical community has little experience. The present study examines the effects of receiving a positive NBS result for PD on families. In-depth qualitative interviews were conducted with mothers of nine children (three IOPD and six LOPD) diagnosed via NBS, exploring their experiences, understanding of PD, how they are coping, and what impact diagnosis is having on family life. Interviews were coded using MaxQDA v.12 and analyzed for thematic trends. While overall opinion of NBS was favorable, it is clear many of the concerns anticipated by HCPs, patients, and families regarding NBS for late-onset LSDs are being realized to varying degrees; LOPD families are becoming patients-in-waiting. Increased fear/anxiety and living with uncertainty (regarding diagnosis, their children's future, and when to start treatment) were predominant themes, with all families voicing considerable emotional reactions and varied social and healthcare support concerns. Coping strategies and psychosocial challenges are interpreted using Rolland & Williams' Family Systems Genetic Illness model. Recommendations for improvement in delivery of service, as well as families' advice for future parents and HCPs, are discussed.

The clinical significance of the c.427G>A (p.A143T) variant in GLA is a topic of debate within the lysosomal storage disease community. A review of the literature and published case reports found the clinical impact of the variant to range from classic Fabry symptoms to healthy unaffected males with normal alpha- galactosidase enzyme levels, leaving clinicians unsure of how to manage these individuals. As the number of states testing for Fabry disease on their newborn screening panel has increased, more people with this variant are being identified. The goal of this project was to learn how the uncertainty surrounding the clinical significance of the p.A143T variant affects those with this change. A self-response questionnaire was developed to explore this topic. In addition to evaluating participant feelings, the questionnaire explored individuals' beliefs regarding the pathogenicity of the variant. Results suggest that people have diverse feelings regarding reclassification of the p.A143T variant. Around half of those surveyed reported feeling frustrated by the lack of clear information. Despite the ambiguity regarding the health consequences of this variant, many participants felt that knowing this result helps guide medical management.

Lysosomal storage diseases (LSDs) are an individually rare but collectively common group of hereditary, progressive, multi-systemic disorders. Recent technological advances have brought newborn screening (NBS) for LSDs to attention in the United States. However, many LSD symptoms present in later childhood or adulthood, with a wide spectrum of severity. Because late-onset symptoms stray from the traditional NBS model, healthcare providers have expressed concerns about potential harm to patients and/or their families. In this study, 47 individuals with Fabry disease (FD), 22 with Gaucher disease (GD), and 22 with late-onset Pompe disease (LOPD) were surveyed regarding how their life might have been impacted by NBS. Of the 91 participants, none had symptoms at birth and 42 (46.7%) were symptom-free until adulthood. Over half (52.8%) were diagnosed ≥5years from symptom onset; of these, significantly more had FD (60%) or LOPD (63.6%) than GD (23.8%). However, length of diagnostic odyssey was not significantly correlated with opinion on NBS. Most participants either strongly agreed (45%) or agreed (33.3%) with NBS for their condition, with no significant differences between diseases. Opinions on NBS were correlated with participants' opinions on whether NBS would have resulted in better current health, but uncorrelated with disease severity or current life satisfaction. Significantly more participants with FD (42.6%) and LOPD (63.6%) than GD (13.6%) felt they would have greater life satisfaction had they been diagnosed as a newborn (p=0.007). Almost half (41%) of participants would have made different life decisions, including lifestyle, financial, and reproductive decisions. Regarding potential harm, participants were most concerned about insurability and least concerned about removal of children's autonomy. In conclusion, NBS is highly approved of among individuals with LSDs themselves, as it would significantly eliminate diagnostic odysseys and potentially alter life planning.

Enzyme replacement therapy (ERT) has led to a significant improvement in the clinical course of patients with infantile Pompe disease (IPD), an autosomal recessive glycogen storage disorder characterized by the deficiency in lysosomal acid α-glucosidase. A subset of IPD patients mounts a substantial immune response to ERT developing high sustained anti-rhGAA IgG antibody titers (HSAT) leading to the ineffectiveness of this treatment. HSAT have been challenging to treat, although preemptive approaches have shown success in high-risk patients (those who are cross-reactive immunological material [CRIM]-negative). More recently, the addition of bortezomib, a proteasome inhibitor known to target plasma cells, to immunotherapy with rituximab, methotrexate, and intravenous immunoglobulin has shown success at significantly reducing the anti-rhGAA antibody titers in three patients with HSAT. In this report, we present the successful use of a bortezomib-based approach in a CRIM-positive IPD patient with HSAT and the use of a preemptive approach to prevent immunologic response in an affected younger sibling. We highlight the significant difference in clinical course between the two patients, particularly that a pre-emptive approach was simple and effective in preventing the development of high antibody titers in the younger sibling, thus supporting the role of immune tolerance induction (ITI) in the ERT-naïve high-risk setting.

Lysosomal storage diseases (LSDs), lysosomal enzyme deficiencies causing multi-system organ damage, have come to the forefront in newborn screening (NBS) initiatives due to new screening technologies and emerging treatments. We developed a qualitative discussion tool to explore opinions of genetic healthcare providers (HCPs) regarding population-based NBS for MPS types 1 and 2, Pompe, Gaucher, Fabry, and Krabbe diseases. Thirty-eight telephone interviews conducted by a single researcher were analyzed and coded for thematic trends. Six major themes emerged: 1) treatment availability and efficacy is crucial; 2) early age of disease onset is important; 3) ambiguity regarding prognosis is undesirable; 4) parents' ability to make reproductive decisions is seen by some as a benefit of NBS; 5) paucity of resources for follow-up exists; and 6) the decision-making process for adding conditions to mandated NBS is concerning to HCPs. Among the LSDs discussed, Pompe was considered most appropriate, and Krabbe least appropriate, for NBS. MPS1 and MPS2 were overall considered favorably for screening, but MPS1 ranked higher, due to a perception of better efficacy of therapeutic options. Fabry and Gaucher diseases were viewed less favorably due to later age of onset. The themes identified in this study must be addressed by decision-makers in expanding NBS for LSDs and may be applied to many diseases being considered for NBS in the future.

Aim Hypotonia is a symptom of diminished tone of skeletal muscle associated with decreased resistance of muscles to passive stretching, which can be caused by abnormalities of the central nervous system, any element of the lower motoneuron, or both. Hypotonia is not a specific diagnosis, but can be part of over 500 different genetic disorders, with many other conditions waiting to be identified. This review proposes a pragmatic approach to evaluating hypotonia in neonatal and pediatric populations by using a diagnostic algorithm. Method We use a dedicated literature review combined with clinical experience in a newly established multidisciplinary center for hypotonia to establish a diagnostic algorithm. Results Hypotonia can be a symptom of over 500 different genetic disorders. It can present as peripheral, central, or combined hypotonia, providing necessity for rational and systematic diagnostic testing. Interpretation Our analyses demonstrate that a staged diagnostic approach categorizing patients as having peripheral, central, or combined hypotonia is the most efficient to providing a rational work-up. Establishing a diagnosis is crucial for prognosis, management, and treatment strategies, and for ascertaining an accurate recurrence risk for future offspring in a family.

An inherited, interstitial subtelomere deletion of approximately 1.3-1.4 Mb at 3q29 was identified in a patient and his father utilizing BAC array comparative genomic hybridization (a-CGH). The imbalance was located within the common 3q29 microdeletion syndrome region and shared the distal breakpoint with prior published cases. However, our patient was developmentally normal at 6 months of age and his father is a functional adult, who had mild developmental delay in childhood. They presented with congenital cardiac defects including patent ductus arteriosus. In addition, the patient had subvalvular aortic stenosis and his father had pulmonic stenosis. These defects were not present in most of the previously reported 3q29 microdeletion cases. This case expands the phenotypic findings associated with 3q29 microdeletion syndrome, suggesting an association with cardiac defect. It also raises the possibility of normal cognition in adulthood.

Background Early highly active antiretroviral therapy (HAART), started within the first months of age, has been proven to be the optimal strategy to prevent immunological and clinical deterioration in perinatally HIV-infected children. Nevertheless, data about long-term follow-up of early treated children are lacking. Methods We report data from 40 perinatally HIV-infected-children receiving early HAART, with a median follow-up period of 5.96 years (interquartile range [IQR]:4.21–7.62). Children were enrolled at birth in the Italian Register for HIV Infection in Children. Comparison with 91 infected children born in the same period, followed-up from birth, and receiving deferred treatment was also provided. Results Nineteen children (47.5%) were still receiving their first HAART regimen at last follow-up. In the remaining children the first regimen was discontinued, after a median period of 3.77 years (IQR: 1.71–5.71) because of viral failure (8 cases), liver toxicity (1 case), structured therapy interruption (3 cases), or simplification/switch to a PI-sparing regimen (9 cases). Thirty-nine (97.5%) children showed CD4+ T-lymphocyte values>25%, and undetectable viral load was reached in 31 (77.5%) children at last visit. Early treated children displayed significantly lower viral load than not-early treated children, until 6 years of age, and higher median CD4+ T-lymphocyte percentages until 4 years of age. Twenty-seven (29.7%) not-early treated vs. 0/40 early treated children were in clinical category C at last follow-up (P < 0.0001). Conclusion Our findings suggest that clinical, virologic and immunological advantages from early-HAART are long-lasting. Recommendations indicating the long-term management of early treated children are needed.