American Journal of Medical Genetics Part A最新文献

Turner syndrome, a chromosomal disorder, causes short stature, pubertal arrest, amenorrhea, and infertility in females. Prevalence estimates vary widely; however, reliable estimates are important for public health initiatives. Therefore, a meta-analysis was undertaken. From a total of 875 English-language studies identified for full-text screening in MEDLINE and Embase by two independent researchers using predefined criteria, data were extracted from 28 studies, which were also evaluated for quality; 19 and 8 were selected for the birth and point/period prevalence meta-analyses, respectively (three studies common to both). A random-effects model was used to calculate a pooled effect size. Heterogeneity was measured using Cochran's Q, Higgins I ², Tau-squared, and Tau. The birth prevalence meta-analysis yielded a pooled estimate of 31.5 (95% CI: 18.2-54.7) per 100,000 female live births. Studies from Europe (compared to Asia) and those with a lifetime case ascertainment period (compared to first year) reported significantly higher birth prevalence. Meta-regression analysis indicated that studies with lifetime case ascertainment had 2.69 times higher prevalence. Case ascertainment period, diagnostic method, and geography accounted for ~90% of the variation in the birth prevalence estimates across studies. The pooled estimate of point/period prevalence was 23.1 (95% CI: 11.4-46.8) per 100,000 females.

Genetic contributors to perinatal demise are common but frequently undiagnosed due to clinical and logistical barriers. We aimed to improve access to genetic for intrauterine fetal demise (IUFD), stillbirth, and early neonatal death by developing a multidisciplinary workflow. A working group representing clinical genetics, maternal-fetal medicine, neonatology, pathology, obstetrics, palliative care, laboratories, and health information technology identified barriers and designed solutions for genetic testing in perinatal demise. Tools developed included testing algorithms, specimen collection and handling guides, documentation templates, and electronic health record integration. Case reviews and stakeholder feedback informed iterative refinement. The workflow clarified team roles, timing, and coordination across specialties. Scenario-specific algorithms for stillbirth, neonatal demise, and pediatric genetics consultations guided testing decisions. A specimen-testing matrix linked sample types with available tests and laboratories. Implementation was supported by education and centralized resources. Representative cases demonstrated improved sample collection, diagnostic yield, and family counseling through early communication and defined responsibilities. A multidisciplinary workflow improved the feasibility and consistency of genetic evaluation in perinatal demise. This model may guide other institutions seeking to implement or enhance genetic testing processes for families affected by pregnancy loss or neonatal death.

The early developmental profile of Kleefstra syndrome remains undercharacterized. To address this gap, this study investigated a large clinical cohort of patients with Kleefstra syndrome, characterizing age of achievement of infant/toddler developmental milestones and quantifying language and visual motor developmental quotients (DQs) using the Capute Scales developmental screening tool. We conducted a retrospective chart review on individuals with molecularly confirmed Kleefstra syndrome. We reported age of achievement of motor and language milestones. In a subset of this cohort, we evaluated DQs for language and visual motor skills based on the Capute Scales. Among 100 individuals (43 males, 57 females; median age 9 years), rolling occurred at a median of 6 months, sitting at 10 months, independent walking at 1.96 years, and first words at 24 months. Capute Scales testing (n = 24) showed median DQs as follows: visual motor skills (53, IQR = 42-71), overall language (56, IQR = 42-67), expressive language (52, IQR = 35-60), and receptive language (50, IQR = 42-61). This work quantifies the early developmental profile of Kleefstra syndrome and suggests that developmental delay can be significant from an early age, making early initiation of services such as physical therapy, occupational therapy, and speech therapy crucial to ensuring optimal skills development. This cross-sectional analysis highlights the need for incorporating longitudinal developmental assessments into the clinical care of patients with Kleefstra syndrome-particularly during infancy and early childhood-to ensure that appropriate educational supports are in place.

The 1,4,5-trisphosphate receptor type 1 (ITPR1) gene encodes an endoplasmic reticulum calcium release channel, in which loss-of-function mutations have been associated with spinocerebellar ataxias and related neurological phenotypes. Only one gain-of-function mutation in the highly conserved suppressor domain of ITPR1 has been previously reported. We report a novel de novo ITPR1 variant (p.(Tyr131His)) detected by whole genome sequencing in a child with an unexplained movement disorder, characterized by tremor and dystonia, concurrent with a second diagnosis of Myhre syndrome. The proband's movement disorder characteristics share much overlap with previously reported individuals with suppressor domain variants; however, she does not have ataxia. We provide functional evidence of this variant's gain-of-function consequence via in vitro experiments of inositol 1,4,5-triphosphate-mediated calcium release. Our findings deepen the knowledge of ITPR1-mediated movement disorders, expanding the phenotypic spectrum to include movement disorders without ataxia.

The ciliopathies are a group of genetic disorders caused by defective function of either the primary cilia (a large number) or the motile cilia (a much smaller number). These have been defined as diseases with mutations in genes encoding individual ciliary or cilia-associated proteins. Recently, it has become apparent that the composition of the ciliary membrane influences its function. For instance, the ciliary membrane contains more cholesterol than other regions of the cell membrane and a variety of unique receptors and ion channels. Additionally, it appears that primary cilia have evolved to lower the threshold for activating signal transduction by establishing the environment essential for signaling pathways on a limited portion of the cell surface. By positioning receptors and downstream signaling components in this thin protrusion at a precise time and location within the plasma membrane, the cell can better orient its physiological response to external stimuli. Cholesterol deficiency can alter cilia formation and function with effects on Sonic hedgehog signaling. In this review, we discuss these new concepts and apply them to the developmental disorder Smith-Lemli-Opitz syndrome and the developmental and neurodegenerative disorder Niemann-Pick C disease, demonstrating that they are also ciliopathies.

RASopathies are a clinically and genetically heterogeneous group of conditions caused by pathogenic variants in genes encoding RAS/MAPK pathway components. Liver involvement has been reported, but systematic evaluation of liver involvement in individuals with RASopathies has not been performed, limiting anticipatory guidance and screening development. We aim to characterize liver involvement in RASopathies. The cohort consisted of individuals with molecularly confirmed RASopathy evaluated at a single center between January 2006 and October 2024. Clinical histories were abstracted from the medical record. The cohort included 192 participants. Liver involvement was noted in 36.5%. Neonatal hyperbilirubinemia was present in 33.3%, and 24% required phototherapy, representing a significantly increased risk (OR 7.1, 95% confidence interval [CI] 4.66-10.95, p < 0.0001). Other liver pathology was noted in 15 participants (7.8%), including elevated aminotransferases (n = 9) and cholestasis (n = 7). Participants with BRAF variants were more likely to have cholestasis than those with other genotypes (OR 6.2, 95% CI 1.45-24.03, p = 0.038). Comprehensive evaluation of liver involvement in a large RASopathy cohort revealed a strong association with neonatal liver disease, most commonly hyperbilirubinemia and cholestasis. Evaluation for liver disease may be warranted in infants with RASopathies, especially individuals with BRAF variants.

Neurofibromatosis type 1 (NF1) is a complex multisystem disorder with marked phenotypic heterogeneity and variable expressivity. While its clinical features have been extensively documented in Western populations, data from India remain limited and largely based on smaller cohorts. This study provides a comprehensive description of the NF1 phenotype in an Indian cohort of 72 patients. The study also explored the frequency of NF1 deletions/duplications in NF1 and their contribution to clinical variability. This cohort adds to the limited Indian data on NF1 and highlights the need for molecular testing in routine clinical evaluation. These findings emphasize the importance of region-specific phenotypic profiling and support the integration of genetic insights into individualized patient care.

Radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 (RUSAT-2) is a rare inherited bone marrow failure syndrome characterized by congenital or progressive thrombocytopenia, frequent radioulnar synostosis, and variable multisystem involvement. It is caused by heterozygous germline pathogenic variants in the MDS1 and EVI1 Complex Locus (MECOM) gene, which encodes transcription factors essential for hematopoietic stem cell regulation and embryonic development. Disruption of highly conserved zinc finger domains within MECOM impairs long-term hematopoietic stem cell maintenance, leading to amegakaryocytic thrombocytopenia and, in many cases, progression to pancytopenia. Although MECOM is also implicated in leukemogenesis through somatic dysregulation, germline variants associated with RUSAT-2 result in a distinct developmental and hematologic phenotype with highly variable penetrance and age of onset. As of 2025, there were approximately 66 reported cases of RUSAT-2 reported in the literature, with clinical severity ranging from isolated thrombocytopenia to early-onset bone marrow failure requiring hematopoietic stem cell transplantation. This review summarizes the current understanding of the genetic basis, clinical manifestations, differential diagnosis, clinical course, management considerations, and outstanding mechanistic questions surrounding RUSAT-2.