American Journal of Medical Genetics Part A最新文献

Schmid metaphyseal chondrodysplasia (SMCD, OMIM #156500) is a skeletal dysplasia characterized by progressive short stature, shortening of the tubular bones, and genu varum. In this study, we present the clinical and genetic findings of patients with COL10A1 variants. A total of seven patients from two unrelated families were included, comprising three children and four adults. The mean age was 6.1 years in children and 41.2 years in adults. Short stature was present in all patients except one, with height SDS ranging from -0.6 to -3.7. All patients exhibited genu varum. Radiographic evaluation revealed coxa vara, metaphyseal irregularities of the long bones, and platyspondyly in all patients; shortening of the tubular bones was observed in six patients, and femoral bowing in two patients. Wormian bones were identified in all six patients from Family 1, representing a previously unreported finding. Two patients underwent hemiepiphysiodesis for the treatment of genu varum. Based on the clinical features, SMCD was suspected in all patients. Genetic diagnosis was established using COL10A1 single-gene analysis in two index patients, and the identified variants were subsequently confirmed by Sanger sequencing in family members. In Family 1, a heterozygous likely pathogenic variant in COL10A1, NM_000493.4:c.1744T>G (p.Tyr582Asp), was identified. In Family 2, a homozygous likely pathogenic variant in COL10A1, NM_000493.4:c.1954C>T (p.Leu652Phe), was detected. Segregation analysis demonstrated heterozygosity for the variant in both clinically unaffected parents. Our findings expand the clinical spectrum of SMCD and underscore the importance of integrating clinical and radiographic evaluation with molecular genetic testing for accurate diagnosis. The identification of a homozygous COL10A1 variant in our patient provides additional support for previous reports demonstrating that SMCD can follow both autosomal dominant and autosomal recessive patterns of inheritance.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

Rapid genomic testing (rGT) is increasingly being used as a first-tier test for critically ill individuals. Limited outcome data make ensuring appropriate utilization challenging. This study evaluates ordering trends and factors impacting the diagnostic yield of rGT. A retrospective analysis was performed on rGT orders reviewed between 2020 and 2024. Diagnostic yield, turnaround time (TAT), and clinical status at the time of the result were ascertained through chart review. Of 270 rGT orders, 98% (265/270) were ordered inpatient, and 79% (213/270) were rapid genome sequencing. While rGT utilization increased more than tenfold in the study period, the diagnostic yield declined. The overall diagnostic yield in our cohort was 20% (54/270). Only 10% (27/265) of inpatient cases were both diagnostic and resulted while the individual was still hospitalized. In 2024, the mean laboratory TAT was reduced to 8.6 days (n = 135) from the 2020-2023 average of 12.5 days (n = 135, p < 0.0001). Increased uptake of rGT as a first-tier genetic test suggests a shift toward broad inpatient genetic testing and is associated with a lower diagnostic yield over time. Evidence-based laboratory stewardship should seek to balance expanded access to rGT while maintaining high clinical utility.

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in one of three known genes: ETFA, ETFB, and ETFDH. It can cause multisystem dysfunction, including cardiomyopathy in severe cases. Ketone supplementation has been reported to be beneficial in a few case reports, but its long-term effectiveness remains unclear. We report an infant with a clinical and biochemical diagnosis of MADD who showed a favorable response to ketone supplementation, with marked improvement in severe cardiac dysfunction and sustained near-normal cardiac function and biochemical profiles over 3.5 years. Although genome sequencing did not identify causative variants, RNA sequencing revealed reduced ETFB transcript levels, and western blot analysis showed decreased ETFB protein levels. This case report illustrates MADD without an identified molecular diagnosis and provides evidence that near-absent ETFB expression is likely responsible for his presentation. These observations can guide further studies investigating the transcriptional regulation of ETFB, thereby elucidating an underappreciated molecular mechanism underlying MADD. Initiating metabolic therapy in patients with clinically suspected MADD, even in the absence of a confirmed molecular diagnosis, can be beneficial as suggested by the clinical and biochemical responses to our therapeutic trial.

The 46th Annual David W. Smith (DWS) Workshop on Malformations and Morphogenesis returned to the University of Wisconsin-Madison, a site of singular historical resonance for dysmorphology. The program unfolded across six themes-orofacial morphogenesis, gastrulation and early embryogenesis, tooth morphogenesis/dentition, genitourinary malformations, chromatin remodeling, and cardiovascular disorders-anchored by keynotes and emphasis lectures from Drs. Paul Trainor, Cigall Kadoch, Ophir Klein, Neil Chi, Robert Lipinski, Margaret Adam, and the Founder's Talk by Dr. Marilyn Jones. This narrative report follows the chronological flow of the meeting, providing fuller detail for anchor lectures and synthetic integration of presentations.

Arrhythmias affect approximately half of patients with Costello syndrome (CS, OMIM # 218040), with non-reentrant atrial tachycardia being the most common. This case describes an infant with Costello syndrome carrying the pathogenic HRAS c.34G>A (p.G12S) variant who developed early-onset, drug-refractory multifocal atrial tachycardia (MAT). Despite multiple antiarrhythmic therapies, rhythm control remained inadequate until trametinib was initiated, resulting in rapid resolution of MAT and allowing stepwise discontinuation of adjunct antiarrhythmics. Although MAT did not recur after the MEK inhibitor was stopped, the patient subsequently developed hypertrophic cardiomyopathy only after trametinib was discontinued, suggesting a potential disease-modifying cardioprotective effect during active treatment. This case supports MEK inhibition as a targeted antiarrhythmic strategy in Costello syndrome, with benefits that may extend beyond acute rhythm stabilization to include prevention of cardiac hypertrophy. While spontaneous resolution of MAT can occur in Costello syndrome, the rapid and sustained response in this patient strengthens the hypothesis that trametinib exerts a direct antiarrhythmic effect.

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 48th Annual Meeting at the University of Minnesota in Minneapolis on September 29-October 1, 2025. On the first day of the meeting, Drs. Timothy Cox and Jennifer Fish were honored with Excellence in Craniofacial Research Awards for their exceptional contributions to the field of craniofacial biology. The following 2 days of the meeting featured five sessions that highlighted new discoveries in human genetics, systems biology of craniofacial development and disease, evolutionary connections, signaling mechanisms, and a special session on clinical and patient perspectives. The meeting also featured workshops on scientific writing and the role of artificial intelligence in advancing research and care. A poster session facilitated dynamic and insightful interactions among the 113 attendees, who represented diverse career stages and research backgrounds in developmental biology and genetics, further strengthening the SCGDB community.

Turner syndrome (TS) is associated with thoracic aortopathy and increased risk for aortic dissection, yet the natural history of aortic dilation is not well understood. We performed a retrospective longitudinal study of individuals with TS who participated in the TS Society of the United States Healthy Heart Project between 2003 and 2023. Participants were selected in descending rank order of aortic size index (ASI, > 18) or TS-specific Z-score (< 18) to generate a cohort intentionally enriched for the largest unoperated aortic diameters. Serial echocardiograms were re-measured using standardized techniques. Patient-specific growth rates were estimated using a pooled mixed-effects best-model framework and compared with the entire HHP longitudinal dataset to evaluate trajectories across risk strata. The primary endpoint was a composite of all-cause death, aortic surgery, or aortic dissection. Twenty-nine individuals (20 adults, 9 pediatric) were followed for a median of 13 years. Longitudinal aortic growth was generally slow (≤ 0.018 cm/year), with three rapid and seven mild progressors. No aortic dissections were observed. Clinical events were driven by elective aortic surgery and death. Height-indexed aortic diameter (aortic height index, AHI) demonstrated the strongest association with the composite endpoint, outperforming ASI and TS-specific Z-scores. In a TS cohort enriched for the largest unoperated aortas, baseline aortic size and clinical risk factors rather than growth rate primarily determined clinical outcomes. These findings support an integrated framework for aortic risk assessment in TS.

Achondroplasia is a skeletal dysplasia associated with severe short stature and multisystem complications due to a gain-of-function pathogenic variant in the FGFR3 gene. Vosoritide, a C-type natriuretic peptide analog, has demonstrated efficacy in clinical trials. The objective of this study was to describe the effectiveness, safety, treatment continuity, and caregiver-reported outcomes of vosoritide in routine practice across heterogeneous health systems in Latin America in a real-world context. We conducted a retrospective, multicenter, multinational cohort study including children with molecularly confirmed achondroplasia treated with vosoritide in centers from Argentina, Colombia, Uruguay, Mexico, and Chile. Eligible patients had ≥ 6 months of treatment and at least two anthropometric evaluations. Height, annualized growth velocity (AGV), body proportion measures, treatment interruptions, adverse events, and parent-reported outcomes were analyzed. Fifty-two patients (mean age 5.9 years at treatment initiation) were included, with a mean treatment duration of 539 days and high adherence (93.9% time without interruptions). Height Z-scores increased significantly from 6 to 36 months (0.33 to 1.58; p < 0.001 to p < 0.05). The most significant impact in AVG is observed during the first year of treatment with vosoritide, followed by a subsequent stabilization, reaching growth rates comparable to those of the healthy population. Increases were consistent across sexes and age groups. All patients were in a higher percentile range for AGV during treatment compared to before treatment, in some cases exceeding the 95th percentile, when compared to reference curves. Body proportion indices remained stable. All patients demonstrated gains in linear growth, although the magnitude of increase varied across individuals. Adverse events were frequent but mild, mainly injection-site reactions; no severe adverse events or treatment discontinuations due to safety issues occurred. Parent-reported outcomes were highly favorable, with 98% of caregivers perceiving positive changes in their children's overall well-being, daily functioning, or quality of life, and all caregivers expressing willingness to recommend the treatment. In real-world clinical practice across Latin America, vosoritide demonstrated rapid and sustained gains in linear growth, favorable tolerability, high adherence, and meaningful benefits as perceived by caregivers. These results reinforce the generalizability of vosoritide therapy in heterogeneous healthcare systems and highlight the relevance of real-world evidence for informing treatment decisions in rare diseases.