Schimmenti, Lisa A.

Abstract Purpose This study describes the structure and timing of the clinical education components of MD-PhD programs to illustrate how variations in preclerkship curriculum correlate with the opportunity for early clinical exposure and other key program characteristics. Method A survey was disseminated to U.S. MD-PhD programs on May 25, 2022, asking about the preclerkship curriculum length (long [> 18 months], medium [13–18 months], or short [12 months]), United States Medical Licensing Examination Step 1 timing (relative to the PhD training and clerkships), and opportunity for clerkships before the PhD phase. This survey was supplemented with data from publicly available sources to include 92 MD-PhD programs. Results This study found a wide range of MD-PhD clinical curricula. A strong association was found between shorter preclerkship curriculum length and the opportunity for clerkships before the PhD (10 of 50 programs [20%] with long preclerkship curriculum, 19 of 35 programs [54%] with medium preclerkship curriculum, and 7 of 7 programs [100%] with short preclerkship curriculum; P < .001). Variations in United States Medical Licensing Examination Step 1 timing also exist based on preclerkship curriculum length and the opportunity for clerkships before the PhD. Shorter preclerkship curriculum length was associated with National Institutes of Health funding of the MD-PhD program (20 [40%] of long, 25 [69%] of medium, and 6 [86%] of short preclerkship curricula; P = .006) and larger MD-PhD program size (35 students with long, 70 with medium, and 86 with short preclerkship curricula; P < .001). Preclerkship curriculum length was not associated with public vs private medical schools, although the West had shorter preclerkship curricula. Conclusions This study underscores the need for collaborative efforts to gain insights into the effectiveness and implications of educational interventions in MD-PhD programs, ultimately informing future training strategies and policies.

Objective This study aimed to determine the prevalence and heteroplasmy level(s) of MT-RNR1 variants m.1555A > G and m.1494C > T, which are associated with aminoglycoside-induced hearing loss, in a general perinatal population. This study also aimed to characterize the association of these variants and their heteroplasmy levels with hearing loss outcomes with and without aminoglycoside exposure. Study Design Droplet digital polymerase chain reaction was performed on 479 maternal DNA samples from a general perinatal biobank at our institution to detect the presence and heteroplasmy levels of MT-RNR1 variants m.1555A > G and m.1494C > T. Testing of paired neonatal specimen(s) was planned for positive maternal tests. A retrospective chart review was performed to characterize the population, identify aminoglycoside exposures, and determine hearing outcomes. Results All maternal samples tested negative for MT-RNR1 variants m.1555A > G and m.1494C > T. Maternal and neonatal subjects had high rates of aminoglycoside exposure (15.9 and 13.9%, respectively). No subjects with sensorineural or mixed hearing loss had documented aminoglycoside exposure. Conclusion This study demonstrated that a larger sample size is needed to establish the prevalence of these variants as no subjects tested positive. Determination of variant prevalence in the neonatal population, association of variant heteroplasmy levels with hearing outcomes, and reliability of maternal testing as a surrogate for neonatal testing are important next steps toward universal prenatal or newborn screening. Key Points

AbstractMyhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies.

Germline 3q21 chromosome deletions result in a rare multi-system condition. Of the 14 cases of germline 3q21 deletion syndrome reported, 2 have been reported to develop myelodysplastic syndrome necessitating allogeneic HCT (our patient and one other). Our patient was treated with an allogeneic, matched sibling hematopoietic cell transplantation. Patients with 3q21 deletion have a predilection for myelodysplastic syndrome, likely due to GATA2 deletion. We recommend frequent complete blood count evaluation with annual bone marrow aspiration to monitor for development of MDS in patients with 3q21 deletion.

AbstractAxenfeld‐Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes.

Objectives: Sensorineural hearing loss (SNHL) occurs commonly as part of mitochondriopathies and varies in severity and onset. In this study, we characterized hearing with specific consideration for hearing loss as a potential early indicator of mitochondrial disease (MD). We hypothesize that genetic testing at the earliest detection of SNHL may lead to an earlier MD diagnosis. Design: We reviewed the clinical and audiometric data of 49 patients undergoing genetic testing for MD. Results: One-third of individuals with molecularly confirmed MD presented with SNHL. On average, patients had hearing loss at least 10 years before genetic testing. The collective audiometric profile includes mild to moderate SNHL at lower frequencies and moderate SNHL at 2 kHz and higher frequencies. Conclusions: This study suggests that screening for SNHL could be an early indicator of MD. We propose that the audiometric profile for those with a MD diagnosis may have clinical triage utility.