Increased frequency of clonal hematopoiesis of indeterminate potential in Bloom syndrome probands and carriers.

Not available.

Bloom syndrome patients and mice display accelerated epigenetic aging.

Bloom syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM gene, which is involved in genome stability. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Interestingly, patients with BSyn do not have other signs of premature aging such as early, progressive hair loss and cataracts. We set out to determine epigenetic age in BSyn, which can be a better predictor of health and disease over chronological age. Our results show for the first time that patients with BSyn have evidence of accelerated epigenetic aging across several measures in blood lymphocytes, as compared to carriers. Additionally, homozygous Blm mice exhibit accelerated methylation age in multiple tissues, including brain, blood, kidney, heart, and skin, according to the brain methylation clock. Overall, we find that Bloom syndrome is associated with accelerated epigenetic aging effects in multiple tissues and more generally a strong effect on CpG methylation levels.

Patterns of multiple congenital anomalies in the National Birth Defect Prevention Study: Challenges and insights.

BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.

A 12-Day-Old Female with Hypothermia, Hypoglycemia and Hyperbilirubinemia.

A 12-day-old, full-term female, born small for gestational age, presented to the emergency department with a 1-week history of worsening hyperbilirubinemia, intermittent hypoglycemia, and episodic hypothermia. The baby's emergency department evaluation revealed transaminitis, pneumatosis intestinalis, indirect hyperbilirubinemia, and hypoglycemia. She was admitted to the ICU and received intravenous glucose, bowel rest, and phototherapy. Thyroid-stimulating hormone, thyroxine, and cortisol levels were low, and growth hormone was undetectable. The patient was hospitalized for a total of 19 days and was discharged from the hospital.

Age of first cancer diagnosis and survival in Bloom syndrome.

PURPOSE: This study aimed to describe the spectrum of cancers observed in Bloom Syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome as these are not well-defined. METHODS: Data from the Bloom Syndrome Registry (BSR) was used for this study. Cancer history, ages of first cancer diagnosis, and ages of death were compiled from the BSR and analyzed. RESULTS: Among the 290 individuals in the BSR, 155 (53%) participants developed 251 malignant neoplasms; 100 (65%) were diagnosed with 1 malignancy, whereas the remaining 55 (35%) developed multiple malignancies. Of the 251 neoplasms, 83 (33%) were hematologic and 168 (67%) were solid tumors. Hematologic malignancies (leukemia and lymphoma) were more common than any of the solid tumors. The most commonly observed solid tumors were colorectal, breast, and oropharyngeal. The cumulative incidence of any malignancy by age 40 was 83%. The median survival for all participants in the BSR was 36.2 years. There were no significant differences in time to first cancer diagnosis or survival by genotype among the study participants. CONCLUSION: We describe the spectrum of cancers observed in Bloom syndrome and the observed survival and age of first cancer diagnosis in Bloom syndrome. We also highlight the significant differences in survival and age of diagnosis seen among different tumor types and genotypes.

Familial colloid cysts: not a chance occurrence.

PURPOSE: Colloid cysts are rare, benign brain tumors of the third ventricle with an estimated population prevalence of 1 in 5800. Sudden deterioration and death secondary to obstructive hydrocephalus are well-described presentations in patients with a colloid cyst. Although historically conceptualized as driven by sporadic genetic events, a growing body of literature supports the possibility of an inherited predisposition. METHODS: A prospective registry of patients with colloid cysts was maintained between 1996 and 2021. Data pertaining to a family history of colloid cyst was collected retrospectively; self-reporting was validated in each case by medical record or imaging review. Frequency of patients with a documented first-degree family member with a colloid cyst based on self-reporting was calculated. The rate of familial co-occurrence within our series was then compared to a systematic literature review and aggregation of familial case studies, as well as population-based prevalence rates of sporadic colloid cysts. RESULTS: Thirteen cases with affected first-degree relatives were identified in our series. Of the entire cohort, 19/26 were symptomatic from the lesion (73%), 12/26 (46.2%) underwent resection, and 2/26 (7.7%) had sudden death from presumed obstructive hydrocephalus. The majority of transmission patterns were between mother and child (9/13). Compared with the estimated prevalence of colloid cysts, our FCC rate of 13 cases in 383 (3.4%) estimates a greater-than-chance rate of co-occurrence. CONCLUSION: Systematic screening for FCCs may facilitate early recognition and treatment of indolent cysts, thereby preventing the rapid deterioration that can occur with an unrecognized third ventricular tumor. Furthermore, identifying a transmission pattern may yield more insight into the molecular and genetic underpinnings of colloid cysts.

Descriptive and risk factor analysis of infantile cataracts: National Birth Defects Prevention Study, 2000-2011.

Using National Birth Defects Prevention Study (NBDPS) data, we sought to estimate birth prevalence, describe clinical characteristics, and examine risk factors for infantile cataracts. We calculated birth prevalence using the numbers of NBDPS-eligible cataract cases and live births in the study area. We described case infants by the presence of associated ipsilateral eye defects (IEDs) and non-eye-related major birth defects. Using maternal exposure information collected via telephone interview, we conducted logistic regression analyses among the interviewed cases and controls. Birth prevalence of infantile cataracts was 1.07/10,000 live births. Unilateral cataracts were more often associated with IEDs, while infants with bilateral cataracts were more often preterm, full-term with low birth weight, or had non-eye-related major birth defects. Unilateral cataracts were positively associated with maternal nulliparity (adjusted odds ratio [aOR] = 1.61, 95% confidence interval [CI] = 1.18, 2.20; reference: multiparity), whereas bilateral cataracts were positively associated with maternal education <12 years (aOR = 2.08, 95% CI = 1.13, 3.82; reference: education >12 years), and foreign-born nativity (aOR = 1.92, 95% CI = 1.04, 3.52; reference: U.S.-born nativity). The current analysis can inform future epidemiological studies aimed at identifying mechanisms underlying the associations between infantile cataracts and complex maternal exposures, such as lower levels of education and foreign-born nativity.

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Rapid genotype imputation from sequence with reference panels.

Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data.

Left ventricular dysfunction in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy is associated with progressive cardiorespiratory failure, including left ventricular dysfunction. METHODS AND RESULTS: Males with probable or definite diagnosis of Duchenne muscular dystrophy, diagnosed between 1 January, 1982 and 31 December, 2011, were identified from the Muscular Dystrophy Surveillance Tracking and Research Network database. Two non-mutually exclusive groups were created: patients with ≥2 echocardiograms and non-invasive positive pressure ventilation-compliant patients with ≥1 recorded ejection fraction. Quantitative left ventricular dysfunction was defined as an ejection fraction <55%. Qualitative dysfunction was defined as mild, moderate, or severe. Progression of quantitative left ventricular dysfunction was modelled as a continuous time-varying outcome. Change in qualitative left ventricle function was assessed by the percentage of patients within each category at each age. Forty-one percent (n = 403) had ≥2 ejection fractions containing 998 qualitative assessments with a mean age at first echo of 10.8 ± 4.6 years, with an average first ejection fraction of 63.1 ± 12.6%. Mean age at first echo with an ejection fraction <55 was 15.2 ± 3.9 years. Thirty-five percent (140/403) were non-invasive positive pressure ventilation-compliant and had ejection fraction information. The estimated rate of decline in ejection fraction from first ejection fraction was 1.6% per year and initiation of non-invasive positive pressure ventilation did not change this rate. CONCLUSIONS: In our cohort, we observed that left ventricle function in patients with Duchenne muscular dystrophy declined over time, independent of non-invasive positive pressure ventilation use. Future studies are needed to examine the impact of respiratory support on cardiac function.

De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

Descriptive and risk factor analysis of nonsyndromic sacral agenesis: National Birth Defects Prevention Study, 1997-2011.

Sacral agenesis is a rare birth defect characterized by partial or complete absence of the sacrum. We sought to (a) describe case characteristics, (b) estimate birth prevalence, and (c) identify risk factors for nonsyndromic sacral agenesis using data from the National Birth Defects Prevention Study (NBDPS). The NBDPS was a population-based, case-control study involving pregnancies with estimated dates of delivery from October 1997 through December 2011. We estimated birth prevalence using all NBDPS eligible cases. Using self-reported maternal exposure information, we conducted multivariable logistic regression analysis to identify potential risk factors overall and among women without diabetes. The birth prevalence of sacral agenesis was 2.6/100,000 live births. In the multivariable analysis, multifetal pregnancy, pre-existing Type 1 diabetes, and pre-existing Type 2 diabetes were positively and significantly associated with sacral agenesis, albeit estimates were imprecise. Preexisting Type 1 diabetes was the strongest risk factor (adjusted odds ratio = 96.6, 95% confidence interval = 43.5-214.7). Among women without diabetes, periconceptional smoking was positively and significantly associated with sacral agenesis. Our findings underscore the importance of smoking cessation programs among women planning pregnancy and the importance of better understanding the role of glycemic control before and during pregnancy when designing interventions for primary prevention of sacral agenesis.

Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant.

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

Palliative care services in families of males with muscular dystrophy: Data from MD STARnet.

INTRODUCTION: Information on use of palliative care services among individuals with Duchenne and Becker muscular dystrophy is scant despite the clearly documented need. METHODS: We examined associations between uptake of palliative care services by 233 males with Duchenne and Becker muscular dystrophy aged 12 and older for both caregiver and affected male characteristics using the Muscular Dystrophy Surveillance Tracking and Research Network baseline interview. RESULTS: Ninety-one percent of caregivers (213/233) used at least one palliative care service. Case management had the highest frequency of use (59%). Use of palliative care was more frequently associated with the characteristics of affected males, as were some individual palliative care services. Utilization of six individual services differed among Muscular Dystrophy Surveillance Tracking and Research Network sites. While research suggests that pain is a frequent problem in Duchenne and Becker muscular dystrophy, only 12.5% reported use of pain management services. DISCUSSION: Although palliative care use among families of males with Duchenne and Becker muscular dystrophy is high overall, there is much variability in use of individual services. Use of palliative care is driven by disease experience in the affected male. Many of the care recommendations for these individuals highlight the importance for early involvement of palliative care professionals.

A Review of MD STAR net's Research Contributions to Pediatric-Onset Dystrophinopathy in the United States; 2002-2017.

Population studies of rare disorders, such as Duchenne and Becker muscular dystrophies (dystrophinopathies), are challenging due to diagnostic delay and heterogeneity in disorder milestones. To address these challenges, the Centers for Disease Control and Prevention established the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STAR net) in 2002 in the United States. From 2002 to 2012, MD STAR net longitudinally tracked the prevalence, clinical, and health care outcomes of 1054 individuals born from 1982 to 2011 with pediatric-onset dystrophinopathy through medical record abstraction and survey data collection. This article summarizes 31 MD STAR net peer-reviewed publications. MD STAR net provided the first population-based prevalence estimates of childhood-onset dystrophinopathy in the United States. Additional publications provided insights into diagnostic delay, dystrophinopathy-specific growth charts, and health services use. Ongoing population-based surveillance continually improves our understanding of clinical and diagnostic outcomes of rare disorders.

Diagnostic Accuracy of Phenotype Classification in Duchenne and Becker Muscular Dystrophy Using Medical Record Data1.

Dystrophinopathies are caused by mutations in DMD resulting in progressive muscle weakness. They are historically divided into the more severe Duchenne (DMD) and milder Becker (BMD) muscular dystrophy phenotypes. Classification is important for research and clinical care. The purpose of this study was to describe a multi-variable approach to classifying cases from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) and to assess the accuracy of the diagnostic classification scheme. We used age at loss of mobility, molecular testing results, and age at symptom onset to classify cases as having DMD or BMD and to assess sensitivity and specificity. Mobility status showed low sensitivity and high specificity for predicting DMD (65.5% and 99.3%, respectively) and BMD (62.8% and 97.7%, respectively) phenotypes. Molecular testing showed 90.9% sensitivity and 66.4% specificity for DMD; 76.3% sensitivity and 90.0% specificity for BMD. Age of onset predicted DMD with sensitivity of 73.9% and specificity of 69.0%; BMD had 99.7% specificity and 36.7% sensitivity. Mobility status, molecular test results, and age at symptom onset are important but inconsistent measures for accurately classifying individuals into DMD or BMD phenotypes. These results have implications for prognosis in newly diagnosed individuals and for classifying phenotype in clinical trials.

Descriptive epidemiology of cerebellar hypoplasia in the National Birth Defects Prevention Study.

BACKGROUND: Cerebellar hypoplasia is a rare disorder of cerebellar formation in which the cerebellum is not completely developed, smaller than it should be, or completely absent. The prevalence of cerebellar hypoplasia at birth is unknown, and little is known about epidemiological risk factors. Using data from the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study, we analyzed clinical features and potential risk factors for nonsyndromic cerebellar hypoplasia. METHODS: The NBDPS included pregnancies with estimated delivery dates from 1997-2011. We described clinical features of cerebellar hypoplasia cases from the study area. We explored risk factors for cerebellar hypoplasia (case characteristics, demographics, pregnancy characteristics, maternal health conditions, maternal medication use, and maternal behavioral exposures) by comparing cases to non-malformed live born control infants. We calculated crude odds ratios (ORs) and 95% confidence intervals using logistic regression models. RESULTS: We identified 87 eligible cerebellar hypoplasia cases and 55 mothers who participated in the NBDPS. There were no differences in clinical features between interviewed and non-interviewed cases. Cerebellar hypoplasia cases were more likely than controls to be from a multiple pregnancy, be born preterm, and have low birth weight. Cerebellar hypoplasia cases were more likely to be born in or after 2005, as opposed to earlier in NBDPS. We found elevated ORs that were not statistically significant for maternal use of vasoactive medications, non-Hispanic black mothers, and mothers with a history of hypertension. CONCLUSIONS: Although unadjusted, our findings from a large, population-based study can contribute to new hypotheses regarding the etiology of cerebellar hypoplasia.

Maternal antihypertensive medication use and selected birth defects in the National Birth Defects Prevention Study.

BACKGROUND: There are limited data on the relationship between antihypertensive medication use in early pregnancy and risk of birth defects. METHODS: Using data from the National Birth Defects Prevention Study, we examined associations between specific antihypertensive medication classes and 28 noncardiac birth defects. We analyzed self-reported data on 17,038 case and 11,477 control pregnancies with estimated delivery dates during 1997-2011. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals, adjusted for maternal age, race/ethnicity, body mass index, parity, pregestational diabetes, and study site, for associations between individual birth defects and antihypertensive medication use during the first trimester of pregnancy. We compared risk among women reporting early pregnancy antihypertensive medication use to normotensive women. RESULTS: Hypertensive women who reported early pregnancy antihypertensive medication use were more likely to be at least 35 years old, non-Hispanic Black, obese, multiparous, and to report pregestational diabetes than normotensive women. Compared to normotensive women, early pregnancy antihypertensive medication use was associated with increased risk of small intestinal atresia (adjusted OR 2.4, 95% CI 1.2-4.7) and anencephaly (adjusted OR 1.9, 95% CI 1.0-3.5). Risk of these defects was not specific to any particular medication class. CONCLUSIONS: Maternal antihypertensive medication use was not associated with the majority of birth defects we analyzed, but was associated with an increased risk for some birth defects. Because we cannot entirely rule out confounding by the underlying hypertension and most ORs were based on small numbers, the increased risks observed should be interpreted with caution.