Cold Spring Harbor Molecular Case Studies

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS , has proven instrumental in confirming the diagnosis and facilitating family studies...

The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which shares a somatic mutation profile in common with other hematopoietic malignancies, has been reported to occur alongside myeloid neoplasms or clonal B-cell proliferations, with identical mutations occurring in more than one cell lineage. Here we report such a case of an elderly woman who was diagnosed over a period of 8 years with diffuse large B-cell lymphoma, polycythemia vera, and AITL, each harboring identical somatic mutations in multiple genes...

We present a unique case of a single patient presenting with two mutationally distinct, PD-L1+ diffuse large B-cell lymphomas (DLBCLs). One of these DLBCLs demonstrated exceptionally high mutational burden (eight disease-associated variants and 41 variants of undetermined significance) with microsatellite instability (MSI) and an acquired PMS2 mutation with loss of PMS2 protein expression, detected postchemotherapy. This report, while highlighting the extent of possible tumor heterogeneity across separate clonal expansions as well as possible syndromic B-cell neoplasia, supports the notion that, although rare, PD-L1 expression and associated states permissive of high mutational burden (such as mismatch repair gene loss of function/MSI) should be more routinely considered in DLBCLs...

This clinical review is designed to assist the pediatrician, family physician or internist in caring for the child, adolescent, adult and family in whom a diagnosis of 16p11.2 deletion syndrome has been confirmed by chromosome analysis. Although a pediatrician's initial contact with the child is usually within the first 5 years of life, occasionally an adolescent or adult will be tested and diagnosed after their sibling or child has been diagnosed with the same condition. Age specific guidance for the clinician is provided in Supplement Fig 1...

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and C-terminus regulatory domains modulate its tumor suppressor activities. In this study we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation...

Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared to the general population. Yet, little is known about the underlying molecular heterogeneity within the veteran population, and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the national Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration resistant...

Metastatic porocarcinomas (PC) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PC. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations...

T-lymphoblastic lymphoma is the most common lymphoblastic lymphoma in children, and often presents with a mediastinal mass. Lymphomatous suprarenal masses are possible but rare. Here we discuss the case of a previously healthy 3-year-old male who presented with mediastinal T-lymphoblastic lymphoma (T-LLy) with bilateral suprarenal masses. Following initial treatment, surgical biopsy of persisting adrenal masses revealed bilateral neuroblastoma (NBL). A clinical genetics panel for germline cancer predisposition did not identify any pathogenic variants...

While the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-year development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment...

ITPR1 is an endoplasmic reticulum-bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C>T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and intellectual disability, as well as craniofacial involvement; an uncommon finding in patients with SCA29...

Anorectal malformations (ARM) constitute a group of congenital defects of the gastrointestinal and urogenital systems. They affect males and females, with an estimated worldwide prevalence of 1 in 5,000 live births. These malformations are clinically heterogeneous and can be part of a syndromic presentation (Syndromic ARM) or as a non-syndromic entity (Non-syndromic ARM). Despite the well-recognized heritability of non-syndromic ARM, the genetic etiology in most patients is unknown. In this study, we describe three siblings with diverse congenital anomalies of the genitourinary system, anemia, delayed milestones, and skeletal anomalies...

Diffuse large B-cell lymphoma (DLBCL) is a very heterogenous group, subdivided into germinal-center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies, including whole exome sequencing (WES) and chromosomal microarrays (CMA), have fostered molecular subclassification of DLBCL, while improving our understanding of their pathogenic mechanisms and resistance to therapy. Here we present distinct case of de novo DLBCL that presented in leukemic form. WES revealed point mutations of CD79B, MyD88, TP53, TBL1XR1 and PIM1 genes, indicating that this lymphoma with leukemic presentation fits the best the MCD/C5 molecular subtype of DLBCL, the prominent subcategory of the ABC DLBCL...

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol-cytochrome c reductase, are particularly rare in humans. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria...

We identified a de novo heterozygous TRPM3 missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy using phenotype-driven prioritization analysis of whole genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to destabilize the protein structure. Our report adds TRPM3 to the list of Mendelian disease-associated genes that can be associated with cerebral palsy and confirms the pathogenicity of the variant p...

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a variant in a single gene, is often uncertain until genetic testing is performed. We report a 13-year-old Korean boy who were initially diagnosed with type 2 diabetes (T2DM). MODY was suspected due to his non-obese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina, San Diego, CA, USA)...

Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-year-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-year-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing (NGS)...

Here, we highlight the case of a 31-year-old man who had clinical features of PHOA and harbored a homozygous variant (c.38C>A, p.Ala13Glu) in the HPGD gene, as indicated by whole exome sequencing (WES). This variant has been previously classified by our laboratory as a VUS. However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c...

Alveolar Capillary Dysplasia (ACD) is a fatal disorder that typically presents in the neonatal period with refractory hypoxemia and pulmonary hypertension. Lung biopsy is traditionally required to establish the diagnosis. We report a 22-month-old male who presented with anemia, severe pulmonary hypertension, and right heart failure. He had a complicated hospital course resulting in cardiac arrest and requirement for extracorporeal membrane oxygenation. Computed tomography (CT) of the chest showed a heterogenous pattern of interlobular septal thickening and pulmonary edema...

PPP2 syndrome type R5D, or Jordan's Syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in PPP2R5D , a beta subunit of the Protein Phosphatase 2A (PP2A) (G. Mirzaa, 2019). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms...

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients self-reported white, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity...