Said Furkan Yildirim

Biallelic germline variants in TP53 are exceedingly rare, and their clinical consequences remain poorly defined. Here, we report a female infant born to consanguineous parents who presented with early-onset, aggressive choroid plexus carcinoma causing death at age 4. Molecular analysis identified a homozygous synonymous variant in the last nucleotide of exon 4 in TP53 (NM_000546.6:c.375G > A, p.Thr125 =). This variant has been previously shown to cause aberrant splicing and partial loss of p53 function, and has been associated with variable penetrance in heterozygous carriers. Both parents, who were first cousins, were heterozygous carriers, and no malignancy history was present at the time of diagnosis. Following identification of carrier status, the couple underwent preimplantation genetic testing and subsequently had a child who did not inherit the familial TP53 variant. This report represents one of the very few documented cases of biallelic TP53 variants and underscores the phenotypic heterogeneity associated with TP53 homozygosity. The case highlights the importance of genetic evaluation in pediatric patients with rare aggressive tumors, particularly in consanguineous families, and demonstrates the critical role of genetic counseling and surveillance in affected relatives.

Background/Objectives: Inherited platelet disorders (IPDs) are diverse conditions characterized by abnormalities in platelet count and function. Next-Generation Sequencing (NGS) shows promise as a diagnostic tool in the diagnosis of IPDs. This study aims to assess the clinical value and limitations of using a targeted NGS panel in diagnosing children with suspected IPDs. Methods: We conducted a retrospective study of 93 children evaluated for suspected IPDs. A targeted NGS panel of 14 IPD-associated genes (RUNX1, WAS, ADAMTS13, ANKRD26, CYCS, GATA1, GP1BA, GB1BB, GP9, ITGA2B, ITGB3, MASTL, MPL, MYH9) was performed. Results: Genetic variants were identified in 30 patients (32.3% of the cohort). A total of 37 variants, of which 15 (40.5%) were novel, were found across 11 of the 14 genes on the panel (all except MPL, CYCS, and RUNX1). Variants were most frequently found in ITGB3 (18.9% of variants), GP1BA (16.2%), and ADAMTS13 (16.2%) genes. The majority of variants (64.9%) were classified as variants of uncertain significance (VUS), followed by likely pathogenic (LP) (27%) and pathogenic (8.1%) variants. Most variants were in a heterozygous state (73%). Specific cases highlighted complex genetic scenarios, such as co-occurring variants, and the identification of pathogenic and LP variants in patients initially presenting with immune thrombocytopenia. Conclusions: NGS helps to identify genetic causes, assess risk, manage, and provide genetic counseling in the management of IPDs. However, the prevalence of VUS underscores the need for a multidisciplinary approach to evaluate NGS results accurately.