Novel neonatal presentation of megalencephaly-polymicrogyria-pigmentary mosaicism syndrome (MPPM) related to MTOR mutation: Report of a case.

The PI3K/AKT/mTOR signaling pathway is a critical mediator of cell functions. Activating mutations of this pathway are known to disturb normal growth and development, leading to a range of overgrowth and neurologic syndromes. We report a case of megalencephaly-polymicrogyria-pigmentary mosaicism syndrome (MPPM) in novel association with MTOR pathogenic variant c.6644C>A (p.Ser2215Tyr) and neonatal evanescent skin findings. This case highlights the importance of a thorough newborn cutaneous examination, as this initial window offers a critical opportunity for potential prognostication and surveillance for neurological sequelae.

Variant ATRX syndrome with dysfunction of ATRX and MAGT1 genes.

A 0.8 kb intronic duplication in MAGT1 and a single base pair deletion in the last exon of ATRX were identified using a chromosome X-specific microarray and exome sequencing in a family with five males demonstrating intellectual disability (ID) and unusual skin findings (e.g., generalized pruritus). MAGT1 is an Mg²âº transporter previously associated with primary immunodeficiency and ID, whereas mutations in ATRX cause ATRX-ID syndrome. In patient cells, the function of ATRX was demonstrated to be abnormal based on altered RNA/protein expression, hypomethylation of rDNA, and abnormal cytokinesis. Dysfunction of MAGT1 was reflected in reduced RNA/protein expression and Mg²âº influx. The mutation in ATRX most likely explains the ID, whereas MAGT1 disruption could be linked to abnormal skin findings, as normal magnesium homeostasis is necessary for skin health. This work supports observations that multiple mutations collectively contribute to the phenotypic variability of syndromic ID, and emphasizes the importance of correlating clinical phenotype with genomic and cell function analyses.

Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.

Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.

Cost Effectiveness of Genomic Population Health Screening in Adults: A Review of Modeling Studies and Future Directions.

BACKGROUND: Detecting actionable health risks for genetic diseases prior to symptomatic presentation at population scale using genomic test technologies is a preventive health innovation being piloted in multiple locations. Standard practice is to screen for risks only in those with personal or family history of specific disease. Genomic population heath screening has proven feasible and potentially scalable. The value of this intervention in terms of economic benefit has been scientifically modeled by several groups. CONTENT: Eight recent cost-effectiveness modeling studies for high penetrance monogenic dominant diseases that used input parameters from 3 different countries are reviewed. Results and their uses in refining implementations are analyzed and the roles for laboratory medicine in facilitating success are discussed. SUMMARY: The reviewed studies generally found evidence for cost-effectiveness of genomic population health screening in at least a subset of their base case screening scenario. Sensitivity analyses identified opportunities for improving the likelihood of cost-effectiveness. On the whole, the modeling results suggest genomic population health screening is likely to be cost-effective for high penetrance disorders in younger adults, especially with achievable reductions in test cost effected partially through combining tests for individual disorders into one screening procedure. Policies founded on the models studied should consider limitations of the modeling methods and the potential for impacts on equity and access in the design and implementation of genomic screening programs.

Growth in perceived clinical genetics competency among primary care providers participating in genomic population health screening.

Limited competency in genetics among primary care providers (PCPs) is a barrier to use of genetic information in healthcare. Formal genetics lessons require time and interest, and knowledge wanes. We hypothesized another path to competency: participation in our PCP-centered adult clinical genomic population health screening program. We asked participating Family Medicine PCPs about their perceptions of growth in their genetics competency. An anonymous, voluntary, cross-sectional survey was developed and distributed to PCPs offering the screening. Results were compiled after 3 weeks. PCPs rated several program resources for value and provided open-ended feedback. Seventy-five percent of respondents agreed that genetics is important to their practice. Eighty-seven percent felt that their knowledge of clinical genetics topics had grown. Eighty-seven percent perceived increased confidence in offering genetic testing and in discussing common genetic results with patients. Respondents gained appreciation for the scope of clinical utility that genetic information offers patients. Each education resource rated at least 3.75 out of 5 for contributing to genetics knowledge. The case-specific Genomic Medicine Action Plan rated highest in educational value, 4.5 out of 5. Most responding PCPs offering genomic population health screening perceived growth in their genetic competency and found hands-on, case-based resources most useful.

Real-World Results from Combined Screening for Monogenic Genomic Health Risks and Reproductive Risks in 300 Adults.

New methods and demonstrations of feasibility guide future implementation of genomic population health screening programs. This is the first report of genomic population screening in a primary care, non-research setting using existing large carrier and health risk gene sequencing panels combined into one 432-gene test that is offered to adults of any health status. This report summarizes basic demographic data and analyses patterns of pathogenic and likely pathogenic genetic findings for the first 300 individuals tested in this real-world scenario. We devised a classification system for gene results to facilitate clear message development for our Genomic Medicine Action Plan messaging tool used to summarize and activate results for patients and primary care providers. Potential genetic health risks of various magnitudes for a broad range of disorders were identified in 16% to 34% of tested individuals. The frequency depends on criteria used for the type and penetrance of risk. 86% of individuals are carriers for one or more recessive diseases. Detecting, reporting, and guiding response to diverse genetic health risks and recessive carrier states in a single primary care genomic screening test appears feasible and effective. This is an important step toward exploring an exome or genome sequence as a multi-purpose clinical screening tool.

Primary Care Implementation of Genomic Population Health Screening Using a Large Gene Sequencing Panel.

To realize the promise of genomic medicine, harness the power of genomic technologies, and capitalize on the extraordinary pace of research linking genomic variation to disease risks, healthcare systems must embrace and integrate genomics into routine healthcare. We have implemented an innovative pilot program for genomic population health screening for any-health-status adults within the largest health system in Vermont, United States. This program draws on key research and technological advances to safely extract clinical value for genomics in routine health care. The program offers no-cost, non-research DNA sequencing to patients by their primary care providers as a preventive health tool. We partnered with a commercial clinical testing company for two next generation sequencing gene panels comprising 431 genes related to both high and low-penetrance common health risks and carrier status for recessive disorders. Only pathogenic or likely pathogenic variants are reported. Routine written clinical consultation is provided with a concise, clinical "action plan" that presents core messages for primary care provider and patient use and supports clinical management and health education beyond the testing laboratory's reports. Access to genetic counseling is free in most cases. Predefined care pathways and access to genetics experts facilitates the appropriate use of results. This pilot tests the feasibility of routine, ethical, and scalable use of population genomic screening in healthcare despite generally imperfect genomic competency among both the public and health care providers. This article describes the program design, implementation process, guiding philosophies, and insights from 2 years of experience offering testing and returning results in primary care settings. To aid others planning similar programs, we review our barriers, solutions, and perceived gaps in the context of an implementation research framework.

Modernizing family health history: achievable strategies to reduce implementation gaps.

Family health history (FHH) is a valuable yet underused healthcare tool for assessing health risks for both prevalent disorders like diabetes, cancer, and cardiovascular diseases, and for rare, monogenic disorders. Full implementation of FHH collection and analysis in healthcare could improve both primary and secondary disease prevention for individuals and, through cascade testing, make at risk family members eligible for pre-symptomatic testing and preventative interventions. In addition to risk assessment in the clinic, FHH is increasingly important for interpreting clinical genetic testing results and for research connecting health risks to genomic variation. Despite this value, diverse implementation gaps in clinical settings undermine its potential clinical value and limit the quality of connected health and genomic data. The NHGRI Family Health History Group, an open-membership, US-based group with international members, believes that integrating FHH in healthcare and research is more important than ever, and that achievable implementation advances, including education, are urgently needed to boost the pace of translational utility in genomic medicine. An inventory of implementation gaps and proposed achievable strategies to address them, representing a consensus developed in meetings from 2019-2020, is presented here. The proposed measures are diverse, interdisciplinary, and are guided by experience and ongoing implementation and research efforts.

Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects.

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.

Identification of novel candidate disease genes from de novo exonic copy number variants.

BACKGROUND: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.

The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients' lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients' LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients' LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome.

Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.

A genotype-first approach for the molecular and clinical characterization of uncommon de novo microdeletion of 20q13.33.

BACKGROUND: Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features. METHODOLOGY/PRINCIPAL FINDINGS: We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions. CONCLUSIONS/SIGNIFICANCE: Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.

IPEX and FOXP3: clinical and research perspectives.

Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immune regulation characterized by the early onset of one or more autoimmune diseases in boys. IPEX is caused by mutations in FOXP3, and is thus the homologue of the scurfy mutant mouse. The gene product, Scurfin, is required for the development of CD4+CD25+ T regulatory cells. In the absence of T regulatory cells, activated CD4+ T cells instigate multi-organ damage resulting in type 1 diabetes, enteropathy, eczema, hypothyroidism, and other autoimmune disorders. While effective therapies are currently limited, studies in the scurfy mouse are revealing aspects of pathophysiology and genetics that will lead to novel approaches for treating IPEX and other autoimmune disorders. Females carrying Foxp3 mutations are unaffected. In new experiments we show that female scurfy mice that are also heterozygous in trans for the X-linked recessive common gamma chain knockout contract autoimmune disease, proving that murine Foxp3 is subject to X-inactivation and providing an example of gene-gene interaction causing autoimmune disease in females. One explanation for the lesser disease severity in these females is proposed.

Meiotic exchange event within the stalk region of an inverted chromosome 22 results in a recombinant chromosome with duplication of the distal long arm.

Meiotic recombination occurs between homologous euchromatic regions of human chromosomes in early meiosis. However, such exchanges have been thought not to occur in the stalk regions of acrocentric chromosomes. We describe a child whose chromosome analysis suggests that crossovers do occur in homologous stalk regions. The proband, initially seen as a term female infant, was born to a 28-year-old mother. Dysmorphic features included wide metopic sutures, low anterior hairline, hypertelorism, external ear malformations, and cleft lip and palate. Blood chromosomes of the proband and parents were studied by G-banding, Q-banding, R-banding, and silver staining. The infant karyotype showed a sub-metacentric chromosome 22; that of the mother showed a pericentric inversion of chromosome 22. Chromosomes of the father were normal. In the infant, the abnormal chromosome 22 long arm appeared normal, but with additional long arm material attached to the distal short arm. In the mother, the distal long arm of the abnormal chromosome 22 was translocated to the distal short arm. The abnormal chromosome stalk in the child was intermediate in size to the stalk size of the abnormal and normal chromosomes 22 in the mother. Fluorescent in situ hybridization (FISH) analysis using chromosome 22 paint and ARSA gene probe confirmed that the duplicated material in the proband was of chromosome 22 origin; the karyotype interpretation is: 46,XX,rec(22)dup(22q)inv(22)(p13q13.1)mat. This abnormal karyotype is most likely due to a crossover event within the inversion loop during meiosis. The stalk length discrepancy suggests that the crossover site occurred in the stalk region.