American Journal of Medical Genetics Part A最新文献

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.

The purpose of this study is to explore the phenotypic spectrum observed in individuals and between families with confirmed variants in the T-Box Transcription Factor 22 gene (TBX22). Pathogenic variants in TBX22 have been identified in individuals with classic X-linked cleft palate (CPX) and also in Abruzzo-Erickson Syndrome (ABERS). We compare the phenotypic features of a newly suspected family with ABERS to those of the original family with ABERS to help determine if family-specific pathogenic variants in TBX22 are the cause of ABERS. Furthermore, we discuss possible mechanisms of action of the identified TBX22 variants. We conducted an observational case series in a new family (Family B) suspected of having ABERS, and a retrospective review of participants in the original family with ABERS (Family A), as described by Abruzzo and Erickson (1977). Thirteen individuals from two different families were included in this case series. As previously reported in 2013, DNA samples from four individuals in Family A were screened for variants in TBX22, and each was found to carry the same unique pathogenic variant. Five individuals from Family B were screened for variants in TBX22, and the four with abnormal features were found to be positive for a new pathogenic variant; however, the variant segregating in this family differed from the one present in Family A. Despite this, there was considerable overlap between Family A and Family B in phenotypic features. Thus, we hypothesize that gain-of-function pathogenic variants in TBX22 are the probable cause of ABERS in both Family A and Family B.

DeSanto-Shinawi syndrome is a rare genetic disorder caused by pathogenic variants or deletions involving the WAC gene, located on chromosome 10p12.1, and is characterized by developmental delay, intellectual disability, and distinctive dysmorphic features. In addition to deletions encompassing WAC, several proximal deletions on chromosome 10 that exclude WAC have also been reported. Here, we describe a patient with a microdeletion of chromosome 10p11.23-p11.21 spanning approximately 4.2 Mb. The patient exhibited intellectual disability, agenesis of the corpus callosum, and congenital heart disease. The deleted region includes the following protein-coding genes: ZNF438, ZEB1, ARHGAP12, KIF5B, EPC1, CCDC7, ITGB1, NRP1, and PARD3, while WAC was preserved. Pathogenic variants or deletions of ZEB1 are known to cause corneal abnormalities and agenesis of the corpus callosum, whereas loss of NRP1 has been implicated in the pathogenesis of congenital heart disease. We therefore hypothesize that haploinsufficiency of multiple genes within the deleted region-particularly ZEB1, EPC1, KIF5B, and NRP1-may collectively contribute to the observed clinical phenotype. These findings suggest that microdeletions involving chromosome 10p11.2 are associated with a phenotype distinct from that of DeSanto-Shinawi syndrome.

TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracellular trafficking, but the full spectrum of pathogenic variants remains poorly understood. We investigated a consanguineous Iranian family with psychomotor delay. Whole exome sequencing (WES) identified a candidate TBCK variant, confirmed by Sanger sequencing. Functional studies were performed using amniotic fluid-derived cell culture, Western blotting, protein structural modeling, and molecular docking analyses. A novel homozygous frameshift variant, TBCK (NM_001163435.3): c.1969dupT (p.Cys657Leufs*17), was detected and absent from population databases. Clinically, the proband presented with severe developmental delay, hypotonia, seizures, and facial dysmorphism, and died at 9 months. Western blotting showed a significant decrease in TBCK expression (p < 0.007). Structural analysis of a theoretically modeled truncated protein indicated C-terminal truncation with loss of critical domains, while in silico docking demonstrated reduced binding affinity between mutant TBCK and Rab1B, suggesting impaired Rab-mediated trafficking. This study reports a novel pathogenic TBCK variant associated with severe neurodevelopmental delay, contributing to the clinical and molecular spectrum of TBCK syndrome. Our findings underscore the importance of genetic testing in rare neurodevelopmental disorders and provide insight into the molecular mechanisms underlying TBCK dysfunction.