American Journal of Medical Genetics Part A最新文献

Craniosynostosis is characterized by premature fusion of cranial sutures, often with a complex genetic basis. While multiple genes have been implicated, the role of TGFBR3 mutations remains largely uncharacterized in human craniosynostosis. We report two Kuwaiti male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low-set ears, undescended testes, and developmental hip dysplasia. Duo whole exome sequencing research re-analysis identified a novel homozygous nonsense variant segregating with the phenotype in TGFBR3 (NM_003243.4: c.2418G>A, p.Trp806Ter), which encodes the betaglycan protein. Functional studies were performed to assess the pathogenicity of the variant. Expression of the mutant TGFBR3 in HEK293T cells demonstrated correct plasma membrane localization but revealed a truncated protein lacking its intracellular C-terminus. The mutant receptor retained canonical co-receptor function. In luciferase reporter assays, both wild-type and mutant TGFBR3 enhanced TGF-β1, TGF-β2, and TGF-β3 signaling. Mutant TGFBR3 produced an increase in luciferase activity relative to wild type only at the highest TGFβ1 concentration tested (10 pM). At lower TGFβ1 concentrations (0.1 and 1 pM) and across all concentrations of TGFβ2 and TGFβ3, mutant and wild-type receptors behaved similarly. This is the first report implicating a biallelic TGFBR3 nonsense variant in a syndromic, autosomal recessive form of craniosynostosis in a Middle Eastern population. The premature stop codon truncates the C-terminal region of the protein, perhaps disrupting critical regulatory or interaction domains. Our results suggest that dysregulated TGFβ signaling via the intracellular C-terminus of the protein may represent a novel pathogenic mechanism in cranial suture biology.

We report an 87-year-old female with a history of intellectual disability, severe speech impairment and behavioral issues. She was globally delayed in childhood. In adolescence, she had hallucinations, behavioral issues and was institutionalized. Her behavioral issues were treated, and her medical and behavioral course was stable until her 80's when she began to decline cognitively. She died at age 87. Exome sequencing revealed a novel predicted damaging missense variant (c.1913T>G; p.Met638Arg; NM_001136196.2) in the gene encoding Transportin-2 (TNPO2). Heterozygous variants in TNPO2 have been recently associated with an intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; MIM:619556). Postmortem pathological examination of her brain revealed focal neuronal depletion in the dentate gyrus, CA1, and hilar regions of the hippocampus. These findings are consistent with human gene expression data showing normal to increased expression of TNPO2 in the dentate gyrus and CA1 region of the hippocampus. We suggest that the p.(Met638Arg) variant in TNPO2 is potentially disease-causing and associated with IDDHISD.

The World Health Organization defines health as "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." Medical interventions are often studied for effectiveness in carefully controlled clinical trials, but the parent-perceived, real-world helpfulness of medical management steps on health is less studied. As part of a broader study to create a valid, reliable health measure in DS, we surveyed caregivers of individuals aged 0-21 with Down syndrome (DS) about activities that were helpful for managing their children's health. From February 2023 to February 2024, we received 542 complete survey responses from a national sample. We present caregiver-reported information on actions that caregivers perceived as helpful to address medical conditions in individuals with DS, medical providers seen, and correlations with general health status. Caregiver reports revealed variable health management actions and diverse perceived helpfulness across health domains. Certain actions for constipation prevention and mental health management correlated with higher overall health scores. The utilization of primary care providers and specialists highlights the importance of interprofessional care and communication. Trial Registration: ClinicalTrials.gov: NCT04631237.

SLC30A9 mutations are linked to Birk-Landau-Perez syndrome, which is characterized by neurodevelopmental and renal disease, thought to result from impaired zinc homeostasis. In this report, we describe a patient with a homozygous likely pathogenic SLC30A9 variant with atypical chorio-retinal degeneration, suggesting retinal involvement in SLC30A9-associated diseases. The patient has bilateral sensorineural hearing loss, developmental delay, intellectual disability, abnormal balance, and Tourette syndrome. Ophthalmic manifestations include vascular attenuation, optic disc pallor, and pigmentation. In addition, the patient is noted to have high myopia. Our case highlights the importance of broad genetic testing in diagnosing rare multi-systemic disorders. Further research into the molecular mechanisms by which SLC30A9 results in photoreceptor disease is essential to understand its role in retinal degeneration and to develop potential therapeutic strategies.

Autosomal recessive spinocerebellar ataxia type 20 (SCAR20) is a rare neurodevelopmental disorder caused by biallelic variants in the SNX14 gene and characterized by developmental delay, hypotonia, cerebellar atrophy, and hearing loss. This study aimed to characterize the clinical, radiological, and genetic presentation of affected individuals in a consanguineous Omani population. We conducted a retrospective and partly prospective case series involving 17 patients from seven consanguineous families seen at the Royal Hospital, Oman. Data were collected between September and November 2024, with historical assessments extending over the past decade. Clinical data were extracted from electronic records, and neuroimaging was reviewed. Whole exome sequencing of seven probands was performed, and familial segregation was confirmed through targeted Sanger sequencing. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines. The most common variant was SNX14 c.647_648del (p.Glu216Valfs24), identified in seven patients. Four patients carried the c.1132C>T (p.Arg378) variant, while two had a novel splice-site mutation, c.613-1G>A. One case involved a contiguous gene deletion affecting NT5E. Patient ages ranged from 1 month to 21 years. This report expands the mutational and clinical spectrum of SCAR20 in the Middle East and highlights the importance of early genetic testing, diagnostic vigilance, and multidisciplinary care in consanguineous populations.

We describe a novel homozygous intragenic deletion in the ALS2 gene in an 8-year-old boy with Infantile-onset Ascending Hereditary Spastic Paraplegia (IAHSP) and oculomotor apraxia, thereby contributing to the expanding genetic landscape of ALS2-related disorders. Comprehensive neurological evaluation, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES) were performed. CMA revealed a run of homozygosity (ROH) at 2q33.1. WES identified a homozygous deletion encompassing exons 24-25 of ALS2, inherited from heterozygous parents. This clinical phenotype was consistent with the IAHSP spectrum, and no previous cases due to intragenic deletion have been reported. Our findings further expand the mutational spectrum of ALS2-related disorders and underscore the relevance of combining CMA and WES in the diagnostic workup of early-onset motor disorders, particularly in consanguineous families and unresolved cases. Greater awareness of rare intragenic deletions may improve early recognition and facilitate accurate genetic counseling in pediatric neurogenetics.

Elective genomic testing (EGT) for medically actionable disease predispositions may help adopted individuals (adoptees) with limited knowledge of family health history (FHH) information understand their inherited risks. In this prospective cohort study, patients who participated in Sanford Health's EGT program were surveyed at the time of enrollment between August 2020 and April 2022 about their motivations for pursuing EGT and perceived risks for three conditions. Data from self-reported adoptees and nonadoptees were analyzed using bivariate analyses. Of the 5799 eligible patients, 197 (3.4%) reported that they were adopted. Adoptees were more likely than nonadoptees to report lack of information about FHH as a very important motivation for pursuing EGT (81% vs. 32%, p < 0.001) and were more likely to rate it as their most important motivation (45% vs. 5%; p < 0.001). Other motivations, including learning about personal disease risk (72% vs. 61%; p = 0.016) and providing disease risk information to children (69% vs. 57%; p = 0.003), were also more likely to be rated as very important by adoptees than by nonadoptees, respectively. No differences in risk perceptions were observed. A lack of FHH information is an important reason why adoptees pursue EGT. Adoptees may hope that EGT will identify inherited risks for disease.

Nance-Horan syndrome (NHS; OMIM 302350) is a rare, X-linked syndrome characterized by bilateral congenital cataracts leading to profound vision loss, specific dental anomalies including characteristic screwdriver blade-shaped incisors, facial anomalies, and intellectual disability. It is caused by deleterious loss of function variants or deletions involving the NHS gene at Xp22.13. Heterozygous females often present with similar, but less severe features than affected males. We describe a relatively large cohort of eight new patients with NHS, including two patients with microdeletions including NHS who had classical presentations, and provide detailed descriptions of the clinical findings for both affected males and females. The spectrum of clinical features in NHS is variable and can be mild, in particular for females, and the condition can remain undiagnosed. This report contributes to the delineation of the phenotypic and genotypic findings associated with this condition.

FRMPD4, a gene on the X-chromosome, encodes a neuronal scaffold protein, and six variants in this gene have been associated with X-linked neurodevelopmental disorder. We identified a novel intronic hemizygous variant (NM_014728.3:c.1198-6C>A) in FRMPD4 in a 2-year-old male patient with moderate developmental delay inherited from his asymptomatic heterozygous mother. Minigene assays in different cell lines demonstrated that this variant led to the consistent skipping of in-frame exon 12, which encodes 30 amino acids within the FERM domain. We speculated that this splicing defect may be due to the impaired recruitment of essential splicing factor U2AF2, as this C>A intronic variant is positioned at the center of the uridine-rich polypyrimidine tract, adjacent to the 3'-splice site. Structural modeling predicted that the loss of this region would disrupt the integrity of the FERM domain. Given that FRMPD4 mediates metabotropic glutamate receptor signaling via its FERM domain, we conclude that this intronic variant is likely pathogenic.