Tumor Profile and Neuropsychological Symptoms of a Family with Novel Pathogenic Variant in NF1 Found by an RNA-Based Analysis

Neurofibromatosis 1 (NF1) is a hereditary monogenic disorder. Common symptoms are cafe au lait spots and / or axillary or inguinal freckles, and cutaneous neurofibromas. In a recent population-based study the cancer risk of NF1 patients was twice compared to average population. This is a case report of patients with variable disease in three generations with GIST and various neuropsychologic symptoms in family, and in which the pathogenic NF1 variant was identified first at the RNA level and then at the DNA level. The case report confirms that GIST tumor is a universal symptom in different NF1 PVs and good academic skills can be achieved even if neuropsychological symptoms are challenging.</p

Genetic Susceptibility due to Moderate Breast Cancer Risk Gene CHEK2: a case report

Today we are increasingly interested in finding out the hereditary variants of moderate risk from a cancer patient. Multigene next generation sequencing (NGS) panel technology, massive parallel sequencing, can efficiently and economically analyze genes in 3 to 6 weeks. There are agreed criteria based on which to suspect hereditary breast cancer and thus to make a referral to clinical genetic unit. The topic research subject is to investigate the cancer risk associated with moderate risk genes. Appropriate follow-up recommendations for persons with moderate genetic susceptibility pathogenic variants to breast cancer are updated regularly as scientific research is published. This is a case report on two CHEK2 families in which pathogenic variant in CHEK2 gene does not alone explain the breast cancer risk of the patients. This is also a mini review of genetic susceptibility of CHEK2 moderate breast cancer gene.</p

Genetic Susceptibility to Kidney Cancer

According to the latest knowledge, hereditary kidney cancers may account for 5–8% of all kidney cancers, and it may be more common than previously thought. Hereditary RCC is often characterized by an early age of onset (approximately 45 years), typical histological pattern, and frequently the bilaterality and multicentricity of the primary tumor. Wilms’ tumor (nephroblastoma) is the most common kidney tumor of childhood. More than 15 syndromes with inherited susceptibility to kidney cancer are known, and there are over 25 known genes associated with them. Most of these are dominantly inherited in which the offspring of the proband has a 50% chance of inheriting a gene mutation with susceptibility to kidney cancer. The aggressiveness of hereditary RCCs and recommended surgery varies depending on the syndrome and mutation type. Also, systemic therapy may be optional. Multigene next generation sequencing (NGS) panel technology allows genes of interest to be studied quickly and cost-effectively. Sequencing investigations have improved the accuracy of hereditary cancer diagnoses. Diagnostic utility has been hugely increased by multigene NGS panels. It is important to identify hereditary cancer susceptibility, because the risk of cancer in the mutation carriers can be reduced. In this review article, the latest literature on syndromes subjecting to hereditary kidney cancer and recommended follow-up is summarized

Novel Germline Variant in Tumor Suppressor SMAD3 Gene Associates with Familial Thoracic Aortic Aneurysm and Dissection Syndrome

Pathogenic variant (PV) in tumor suppressor gene SMAD3 (SMAD family member 3) causes dysregulated transforming growth factor-β (TGF-β) signaling. PV in SMAD3 is seen in sporadic cancers as somatic variant but also in germline variant causing hereditary TGF-β vasculopathy with aneurysm condition. The clinical picture of thoracic aortic aneurysm, dilatation or dissection (TAAD) families with SMAD3 PV has been published from the year of 2011. The phenotypic spectrum of SMAD3 PVs has not yet been fully identified. This case report shows the family with novel SMAD3 variant named c.860G>A with very high risk for aortic dissection approximately at the age of 50 years. The result of segregation analysis of the family strongly suggests that this variant is pathogenic. The main symptom in the family is aortic dilatation and aortic dissection.</p

Genetic Susceptibility to Epithelial Ovarian and Endometrial Cancer

Multigene next generation sequencing (NGS) panel technology, massive parallel sequencing, can efficiently and economically analyze genes in 3 to 6 weeks. There are agreed criteria based on which to suspect hereditary ovarian and endometrial cancer and thus to make a referral to clinical genetic unit.The geneticist interprets the genetic results and the information from pedigree. When a person is diagnosed with pathogenic variant (mutation) with genetic susceptibility to ovarian and endometrial cancer, counseling is provided on the associated cancer risk and appropriate monitoring is organized. Healthy family members with mutation can participate in recommended surveillance. Identifying carriers allows treatment and follow-up to reduce the morbidity and mortality for cancer patients and their healthy relatives.This is a case report on gene test results in hereditary breast and ovarian cancer syndrome (HBOC) families who have ovarian cancer in southwestern Finland. And a review of genetic susceptibility to ovarian and endometrial cancer.</p

Perinnöllisyyslääkärin osuus syövän geenidiagnostiikassa - kokemukset Tyksistä ja muualta

Geeniohjatun syövän hoidon työryhmän (MTB) tiimityöskentelyssä perinnöllisyyslääkärien rooliin kuuluu erityisesti geenivarianttien eli geenimuutosten merkitysten tulkinta siitä näkökulmasta, voisiko todettu variantti olla perinnöllinen ituradassa esiintyvä variantti (germline variant) somaattisen sijasta. Uusimpien raporttien mukaan kasvainnäytetutkimusten tulokset viittaavat siihen, että perinnöllisten syöpien osuus kaikista syövistä on aikaisemmin ymmärrettyä suurempi. Esittelemme Tyksin MTB:n päätösten pohjalta kahden vuoden aikana hoidetut 20 potilasta perinnöllisyyslääkärin näkökulmasta. Pilottiaineistossa todettujen perinnöllisten patogeenisten geenivarianttien osuus oli 15 \%, mikä on linjassa uusimpaan kirjallisuustietoon nähden

Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation

Background: Phelan-McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. Method: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings' and the parents' DNA sample. Results: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. Conclusion: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.Peer reviewe

Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation

Background: Phelan-McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. Method: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings' and the parents' DNA sample. Results: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. Conclusion: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.Peer reviewe

Perinnöllisyyslääkärin osuus syövän geenidiagnostiikassa - kokemukset Tyksistä ja muualta

Vertaisarvioitu. Teema : geeniohjatun syövän hoidon työryhmä.Geeniohjatun syövän hoidon työryhmän (MTB) tiimityöskentelyssä perinnöllisyyslääkärien rooliin kuuluu erityisesti geenivarianttien eli geenimuutosten merkitysten tulkinta siitä näkökulmasta, voisiko todettu variantti olla perinnöllinen ituradassa esiintyvä variantti (germline variant) somaattisen sijasta. Uusimpien raporttien mukaan kasvainnäytetutkimusten tulokset viittaavat siihen, että perinnöllisten syöpien osuus kaikista syövistä on aikaisemmin ymmärrettyä suurempi. Esittelemme Tyksin MTB:n päätösten pohjalta kahden vuoden aikana hoidetut 20 potilasta perinnöllisyyslääkärin näkökulmasta. Pilottiaineistossa todettujen perinnöllisten patogeenisten geenivarianttien osuus oli 15 %, mikä on linjassa uusimpaan kirjallisuustietoon nähden.Peer reviewe