A chromoanagenesis-driven ultra-complex t(5;7;21)dn truncates neurodevelopmental genes in a disabled boy as revealed by whole-genome sequencing.

Germline or constitutional chromoanagenesis-related complex chromosomal rearrangements (CCRs) are rare, apparently "all-at-once", catastrophic events that occur in a single cell cycle, exhibit an unexpected complexity, and sometimes correlate with a severe abnormal phenotype. The term chromoanagenesis encompasses three distinct phenomena, namely chromothripsis, chromoanasynthesis, and chromoplexy. Herein, we found hallmarks of chromothripsis and chromoplexy in an ultra-complex t(5;7;21)dn involving several disordered breakpoint junctions (BPJs) accompanied by some microdeletions and the disruption of neurodevelopmental genes in a patient with a phenotype resembling autosomal dominant MRD44 (OMIM 617061). G-banded chromosomes and FISH showed that the CCR implied the translocation of the 5p15.2→pter segment onto 7q11.23; in turn, the fragment 7q11.23→qter of der(7) separated into two pieces: the segment q11.23→q32 translocated onto 5p15.2 and fused to 21q22.1→ter in the der(5) while the distal 7q32→qter segment translocated onto der(21) at q22.1. Subsequent whole-genome sequencing unveiled that CCT5, CMBL, RETREG1, MYO10, and TRIO from der(5), IMMP2L, TES, VPS37D, DUS4L, TYW1B, and FEZF1-AS1 from der(7), and TIAM1 and SOD1 from der(21), were disrupted by BPJs, whereas some other genes (predicted to be haplosufficient or inconsequential) were completely deleted. Although remarkably CCT5, TRIO, TES, MYO10, and TIAM1 (and even VPS37D) cooperate in key biological processes for normal neuronal development such as cell adhesion, migration, growth, and/or cytoskeleton formation, the disruption of TRIO most likely caused the patient's MRD44-like phenotype, including intellectual disability, microcephaly, finger anomalies, and facial dysmorphia. Our observation represents the first truncation of TRIO related to a chromoanagenesis event and therefore expands the mutational spectrum of this crucial gene. Moreover, our findings indicate that more than one mechanism is involved in modeling the architecture of ultra-complex rearrangements.

Clinical Exome Sequencing Enables Congenital Sialidosis Type II Diagnosis in Two Siblings Presenting with Unreported Clinical Features from a Rare Homozygous Sequence Variant p.(Tyr370Cys) in NEU1.

Sialidosis is a rare autosomal recessive disease that presents with progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by homozygous or compound heterozygous sequence variants in the neuraminidase 1 (NEU1) gene. These sequence variants can lead to sialidosis type I and II; the latter is the most severe and presents prenatally or at early age. However, sialidosis diagnosis is challenging, especially in those health systems with limited resources of developing countries. Consequently, it is necessary to dip into high-throughput molecular diagnostic tools to allow for an accurate diagnosis with better cost-effectiveness and turnaround time. We report a 4-member pedigree segregating an ultrarare missense variant, c.1109A>G; p.Tyr370Cys, in NEU1 as detected by whole-exome sequencing. Two short-lived siblings, who presented with previously unreported clinical features from such a homozygous sequence variant, were diagnosed with sialidosis type II. Additionally, we present a novel molecular model exhibiting the consequences of the variant in the sialidase-1 tridimensional structure. This study allowed us to provide a definitive diagnosis for our patients, increase our understanding of this pathogenic variant, and improve genetic counseling.

Breast cancer in males, case presentation and literature review / Cáncer de mama en varones, presentación de caso y revisión de literatura

Background: Male breast cancer is a rare entity, with an approximate rate of 1.1 / 100 000 in the US, with an average age of 67 years. In all cases a genetic study must be performed, in order to find mutations in known genes, and after the resolution of the disease, based on the results, a contralateral prophylactic mastectomy should be considered. Clinical case: 53 -year-old male diagnosed with right breast cancer, infiltrating ductal adenocarcinoma type, clinical stage IIB, breast cancer on 2 immediate family history, mutations of the BRCA1 gene and positive hormone receptors and Her2/Neu. He was treated with modified radical mastectomy in diseased side with subsequent neoadjuvant chemotherapy/radiotherapy. After a year of follow-up and a free behavior of disease, contralateral prophylactic mastectomy was performed. The patient progressed satisfactorily, following up to 18 months since the beginning, with no tumor activity data. Conclusions: Breast cancer in male patient has a worse prognosis than female patients, due to lower amount of tissue in breast exposed to an earlier chest spread and a different biological behavior, also a higher risk of prostate and pancreatic cancer is associated. Studies of adequate methodological quality are scarce, so that decisions are based on guidelines for breast cancer in women.

Introducción: el cáncer de mama en varones es una entidad poco frecuente, con una tasa aproximada de 1.1/100 000 habitantes en los Estados Unidos de América, con una edad media de presentación de 67 años. En todos los casos se aconseja realizar un estudio genético al paciente en búsqueda de mutaciones conocidas y después de la resolución de la enfermedad, con base en los resultados, considerar realizar una mastectomía profiláctica contralateral. Caso clínico: paciente masculino de 53 años de edad, con diagnóstico de cáncer de mama derecha, tipo adenocarcinoma canalicular infiltrante, estadio clínico IIB, con antecedentes de cáncer de mama en 2 familiares directos, mutaciones del gen BRCA1 y positivo tanto a receptores hormonales como para el gen Her2/Neu. Fue tratado con mastectomía radical modificada en lado enfermo con neoadyuvancia subsecuente a base de quimio/radioterapia, tras un año de seguimiento y con un comportamiento libre de enfermedad se realizó mastectomía profiláctica contralateral. El paciente evolucionó satisfactoriamente, en seguimiento a 18 meses sin datos de actividad tumoral. Conclusiones: el cáncer de mama en el paciente varón tiene un pronóstico peor respecto al paciente de sexo femenino, esto por la menor cantidad de tejido en mama que lo expone a una diseminación torácica más temprana y por su comportamiento más agresivo, además de asociarse a un mayor riesgo de desarrollar cáncer de próstata y páncreas, respecto a la población general. Los estudios de adecuada calidad metodológica son escasos, por lo que la toma decisiones se fundamenta en las directrices para el cáncer de mama en mujeres.