The expanded newborn screening (NBS) program in the Russian Federation, launched in 2023, includes the detection of severe forms of T- and B-cell immunodeficiencies via TREC/KREC quantification. We report a rare case of a male infant having multiple congenital anomalies and lymphopenia identified through this program. Genetic testing revealed a 25.8 Mb terminal deletion spanning 13q31.2-qter, consistent with 13q deletion syndrome. Initial NBS revealed reduced TREC levels, prompting further evaluation. The patient exhibited a complex phenotype, including central nervous system malformation (alobar holoprosencephaly), severe congenital heart disease, renal hypoplasia, limb and genitourinary anomalies, and facial dysmorphism. Postnatal complications included pneumonia, pleuritis, and chylothorax. Flow cytometry demonstrated mild T- and B-cell lymphopenia. The genomic defect was characterized using long-read third-generation sequencing, enabling precise breakpoint identification and accurate mapping of deleted genes. The deletion was confirmed via subtelomeric FISH analysis. The patient died at 7 months of age due to the progression of underlying congenital anomalies and associated complications. Our findings broaden the clinical characterization of distal 13q deletion syndrome and demonstrate the value of long-read sequencing in structural chromosomal analysis. They further highlight the difficulties of caring for neonates having complex malformations and immune dysfunction. Given the potential for both primary and secondary immune disturbances, comprehensive immunological evaluation should be considered in patients having 13q deletion syndrome to improve diagnostic accuracy and inform appropriate clinical management.

Chromosome 13q deletion syndrome shows variable clinical features related to the different potential breakpoints in chromosome 13q. The severely malformed phenotype is known to be associated with the deletion of a critical region in 13q32. However, esophageal atresia is a rare symptom and the relevant region is unknown. Thus, determining the association between accurate breakpoints and new clinical features is essential. A 28-year-old Japanese primigravid woman was referred for fetal growth restriction, absence of a gastric bubble, cerebellar hypoplasia, overlapping fingers, and polyhydramnios at 31 weeks gestation. At 38 + 0 weeks, she delivered a 1774 g female infant. The infant presented with isolated esophageal atresia (Gross type A), Dandy-Walker malformation, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. Her karyotype was diagnosed as 46,XX,del(13)(q32.1-qter) by amniocentesis, but array comparative genomic hybridization after birth revealed the deletion of 13q31.3-qter. At 48 days after birth, the infant underwent surgery for esophageal atresia and was later discharged from the hospital at 7 months of age. This case report and the literature reviews supports the previous findings on the pathological roles of haploinsufficiency of the ZIC2/ZIC5 in Dandy-Walker malformation and the EFBN2 haploinsufficiency in eye malformation and hearing loss. Furthermore, the possible involvement of IRS2, COLA1, and COLA2 in eye malformation were identified. This is the first case of 13q deletion syndrome with esophageal atresia (Gross A), but it may be a symptom of VATER/VACTER association (vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects), as in the previous cases. These symptoms might also be associated with EFBN2 haploinsufficiency, although further research is required.

Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes.

Ring chromosomes, which are formed through the fusion of the telomeric ends of a chromosome, present with a spectrum of symptoms whose severity depends on the amount of genetic material lost. Ring chromosome 13 cases present with symptoms similar to that of deletion 13q syndrome, and can be classified depending on whether several critical regions are involved in the deletion. An important region to consider is locus 13q32, whose deletion is known to cause severe phenotypes and major malformations. In contrast, deletions of the more distal locus 13q34 have been shown to be involved in symptoms such as microcephaly and ambiguous genitalia. Herein, we report a case of a pediatric patient with r(13) who presented with microcephaly, facial dysmorphism, hand and feet anomalies, and ambiguous genitalia. The karyotype was described as 46,XY,r(13)(p11.1q34). This case highlights the importance of cytogenetic analysis in determining the prognostic implications of ring chromosome cases.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.