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Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.

Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.

Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up. To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data. We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106). Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included. Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.

The Undiagnosed Diseases Network, an NIH-funded network of seven U.S. sites, accepted 601 patients for evaluation over a 20-month period. Of the 382 patients who had a complete evaluation, 132 (35%) received a diagnosis; 15 of the diagnoses (11%) were made by clinical review alone and 98 (74%) by exome or genome sequencing.

Background The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs. Methods We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs ( n  = 194; 27%) and a cohort whose phenotypes were not explained by an IMD ( n  = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods. Results These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS. Conclusion The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.

Mutations affecting both components of the telomerase enzyme, hTERT and hTR, are associated with familial idiopathic pulmonary fibrosis, and carriers of such mutations have shorter telomeres than do noncarrier family members. This finding suggests that the disease may be triggered by a loss of alveolar cells, the progenitors of which may be limited by short telomeres. Mutations affecting both components of the telomerase enzyme, hTERT and hTR, are associated with familial idiopathic pulmonary fibrosis, and carriers of such mutations have shorter telomeres than do noncarrier family members. Idiopathic pulmonary fibrosis has a predictable, progressive clinical course that ultimately leads to respiratory failure. Irreversible fibrosis is the hallmark of the disease, which has a characteristic radiographic appearance most often associated with the pathological lesion of usual interstitial pneumonia. Although both genetic and environmental factors have been implicated, the cause of idiopathic pulmonary fibrosis is unknown — as, indeed, its name implies. Treatment approaches that target the immune system have not proved to be successful. 1 From 2 to 20% of patients with idiopathic pulmonary fibrosis have a family history of the disease; inheritance appears to be autosomal dominant with . . .

The molecular basis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome remains largely unknown. Pathogenic variants in WNT4 and HNF1B have been confirmed in a small percent of individuals. A variety of copy number variants have been reported, but causal gene(s) remain to be identified. We hypothesized that rare structural variants (SVs) would be present in some individuals with MRKH, which could explain the genetic basis of the syndrome. Large molecular weight DNA was extracted from lymphoblastoid cells from 87 individuals with MRKH and available parents. Optical genome mapping (OGM) was performed to identify SVs, which were confirmed by another method (quantitative PCR, chromosomal microarray, karyotype, or fluorescent in situ hybridization) when possible. Thirty-four SVs that overlapped coding regions of genes with potential involvement in MRKH were identified, 14 of which were confirmed by a second method. These 14 SVs were present in 17/87 (19.5%) of probands with MRKH and included seven deletions, three duplications, one new translocation in 5/50 cells—t(7;14)(q32;q32), confirmation of a previously identified translocation—t(3;16)(p22.3;p13.3), and two aneuploidies. Of interest, three cases of mosaicism (3.4% of probands) were identified—25% mosaicism for trisomy 12, 45,X(75%)/46,XX (25%), and 10% mosaicism for a 7;14 translocation. Our study constitutes the first systematic investigation of SVs by OGM in individuals with MRKH. We propose that OGM is a promising method that enables a comprehensive investigation of a variety of SVs in a single assay including cryptic translocations and mosaic aneuploidies. These observations suggest that mosaicism could play a role in the genesis of MRKH.

Background Sequencing reanalysis can benefit from the inclusion of new information about the patient and from the literature. We studied approaches needed to make reanalysis part of routine follow-up by clinical geneticists. Methods Reanalysis used the SimulConsult diagnostic decision support software, which generates a pertinence metric for gene zygosities determined from the variant table and the patient’s findings. Twenty patients had routine exome sequencing at St. George’s Hospital (London, UK). Twenty were admitted to the Undiagnosed Diseases Network at Vanderbilt University Medical Center (VUMC) and had all remained undiagnosed despite previous evaluations and sequencing. Results For St. George’s cases, reanalysis picked 7 of the 7 initial diagnoses plus 2 diagnoses found later, and suggested another diagnosis with a gene absent from the variant table. For VUMC, reanalysis picked 5 of 8 diagnoses that were in the variant tables, and suggested a non-coding variant absent from the variant table. Conclusion Rapid reanalysis by clinicians could increase the yield of genetic diagnosis with minimal effort and no new lab expenses. For the routine cases at St. George’s, diagnostic yield increased from 7 to 10 (43%). Capabilities that could further increase yield include joint variant calling, robust phenotyping, clinical correlation after sequencing, and adding CNV data to variant tables.

The telomerase reverse transcriptase synthesizes new telomeres onto chromosome ends by copying from a short template within its integral RNA component. During telomere synthesis, telomerase adds multiple short DNA repeats successively, a property known as repeat addition processivity. However, the consequences of defects in processivity on telomere length maintenance are not fully known. Germline mutations in telomerase cause haploinsufficiency in syndromes of telomere shortening, which most commonly manifest in the age-related disease idiopathic pulmonary fibrosis. We identified two pulmonary fibrosis families that share two non-synonymous substitutions in the catalytic domain of the telomerase reverse transcriptase gene hTERT: V791I and V867M. The two variants fell on the same hTERT allele and were associated with telomere shortening. Genealogy suggested that the pedigrees shared a single ancestor from the nineteenth century, and genetic studies confirmed the two families had a common founder. Functional studies indicated that, although the double mutant did not dramatically affect first repeat addition, hTERT V791I-V867M showed severe defects in telomere repeat addition processivity in vitro. Our data identify an ancestral mutation in telomerase with a novel loss-of-function mechanism. They indicate that telomere repeat addition processivity is a critical determinant of telomere length and telomere-mediated disease.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.Achondroplasia is the most common skeletal dysplasia and is characterized by various lifelong clinical, functional and psychosocial challenges for affected individuals. This first International Consensus Statement on the care of children and adults with achondroplasia aims to facilitate the global standardization and improvement of achondroplasia clinical care.