American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

This piece narrates the journey of Maria (name of the mother has been altered to protect the family's privacy), a new mother confronting her newborn's unexpected diagnosis of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, despite undergoing proactive genetic carrier screening within a consanguineous marriage. It highlights the emotional and systemic challenges arising from the lack of diversity in genetic databases, which, in this case, failed to detect pathogenic variants in Maria and her husband. Maria's story sheds light on situations where a masked variant of uncertain significance (VUS) necessitates consultation with a trained genetics specialist and underscores the urgent need for a more equitable healthcare system.

There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis. Affected individuals in six out of eight families (75%) carried homozygous variants that met ACMG criteria for being pathogenic (in the genes ADGRG1, METTL23, SPG11) or likely pathogenic (in the genes GPAA1, MFN2, SGSH). The remaining two families had homozygous candidate variants in the genes (AP4M1 and FAM126A) associated with phenotypes consistent with their clinical presentations, but the variants did not meet the criteria for pathogenicity and were hence classified as variants of unknown significance. Notably, the variants in ADGRG1, AP4M1, FAM126A, and SGSH did not have prior reports in the literature, demonstrating the importance of including diverse populations in genomic studies. We provide clinical phenotyping along with analyses of ES data that support the utility of ES in making accurate molecular diagnoses in these patients, as well as in unearthing novel variants in known disease-causing genes in underrepresented populations from LMIC.

Variants in SCN2A are a known risk factor for developing autism spectrum disorder (ASD). Catatonia is a complex neuropsychiatric syndrome, which occurs at a higher rate in individuals with ASD. Catatonia has also been associated with COVID-19 infection, though the majority of these cases are associated with increased serum inflammatory markers. We present a case of a 15-year-old female with ASD and corticosteroid responsive stuporous catatonia to explore the relationship between SCN2A variants, ASD, COVID-19 exposure, and treatment refractory catatonia. Despite a lack of significantly elevated serum or CSF inflammatory markers, this patient showed significant improvement following initiation of corticosteroid therapy. This case presents a novel approach to the work-up and treatment of catatonia in individuals with SCN2A variants independent of elevated inflammatory markers.

Neurofibromatosis type 1 (NF-1) microdeletion syndrome accounts for 5 to 11% of individuals with NF-1. The aim of our study was to characterize a large cohort of individuals with NF-1 microdeletion syndrome and expand its natural history. We conducted a retrospective chart review from 1994 to 2024 of individuals with NF-1 microdeletion syndrome followed at two large Neurofibromatosis Clinics. This cohort consists of 57 individuals with NF-1 microdeletion syndrome (28 type-1, 4 type-2, 2 type-3, 9 atypical deletions, and 14 indeterminate). We note 38/56 (67.9%) with describable facial features, 25/57 (43.8%) with plexiform neurofibromas, and 3/57 (5.2%) with malignant peripheral nerve sheath tumors within the observed period. The most reported neurodevelopmental manifestations from school-age or older individuals included 39/49 (79.6%) with developmental delays, 35/49 (71.4%) with expressive and/or receptive speech delays, 33/41 (80.5%) with learning difficulties, and 23/42 (54.8%) with attention-deficit/hyperactivity disorder. Full-scale IQ testing data was available for 22 individuals (range: 50-96). Of the 21 adults in this cohort, 14/21 (66.7%) graduated from high school, and 4/21 (19.0%) had some college experience. Many individuals received academic support (i.e., special education, individual education plan). In this cohort, neurocognitive outcomes in adults varied more than typically reported in the literature.