👤 Ali Al-Beshri

Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.21q11.21 correlates with hematologic disorders. We report a 19-year-old female with constitutional mosaic pericentromeric trisomy 8 presenting with menorrhagia, vitamin B12 deficiency, familial short stature, pancytopenia, and bone marrow aplasia. G-banded chromosome and FISH analyses of her bone marrow and blood samples revealed constitutional mosaic pericentromeric trisomy 8. Chromosomal microarray analysis confirmed mosaic duplications in the 8p12q11.21 region spanning 51 OMIM genes, with 16 identified as OMIM morbid genes, and including 9 genes with autosomal dominant inheritance patterns. FGFR1, ASH2L, ANK1, KAT6A, IKBKB, PLAT, and CEBPD are implicated in hematologic disorders, with FGFR1, ASH2L, KAT6A, and IKBKB showing notable triplosensitivity scores. These regions overlap with 13 published cases (12 papers), of which three displayed hematologic disorders, including neutropenia and juvenile myelomonocytic leukemia. Our case underscores the 8p12q11.21 region as a potential causal region for aplastic anemia, emphasizing the need for further investigation of this patient for possible progression to hematologic malignancy. Show less

Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism. Show less