Consensus recommendations of the german consortium for hereditary breast and ovarian cancer

BACKGROUND: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has established a multigene panel (TruRisk®) for the analysis of risk genes for familial breast and ovarian cancer. SUMMARY: An interdisciplinary team of experts from the GC-HBOC has evaluated the available data on risk modification in the presence of pathogenic mutations in these genes based on a structured literature search and through a formal consensus process. KEY MESSAGES: The goal of this work is to better assess individual disease risk and, on this basis, to derive clinical recommendations for patient counseling and care at the centers of the GC-HBOC from the initial consultation prior to genetic testing to the use of individual risk-adapted preventive/therapeutic measures

Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke

Familial breast cancer: Genetic counseling over time, including patients´ expectations and initiators considering the Angelina Jolie effect

<div><p>Purpose</p><p>The German Consortium for hereditary breast/ovarian cancer (GC-HBOC) aims for nationwide access to professional, individualized yet structured care for families at high risk. The identification of such families remains key for optimal care. Our study evaluates counselees’ characteristics, referral practices, expectations and motivations in respect to their first genetic consultation. The impact of the Angelina Jolie Effect (AJE) was prospectively assessed.</p><p>Methods</p><p>All counselees could participate through a questionnaire. Groups were built in respect to neoadjuvant chemotherapy (FT) and before/after AJE.</p><p>Results</p><p>The 917 (88.5%) counselees (FT: 8.2%) were on average female (97.3%), with a mean age of 44.6, had children (71.9%), higher education (88%), personal (46.4%) or at least one first-degree relative (74.6%) with BC/OC or known <i>BRCA1</i>/2 mutation (11.8%), were in a relationship (76.1%), and living in a village (40.7%). The AJE is associated with significantly fewer cancelations (p = 0.005), more attendance among men (4.2% vs. 0.8%, p = 0.002), and people with familial <i>BRCA1/2</i> (14.8% vs. 7.5%, p = 0.003). The majority seek information regarding their cancer risk (83%) or relatives’ risk (74.8%), HBOC (69.1%), and surveillance programs for themselves (66.6%) or relatives (60.6%).</p><p>Conclusion</p><p>Enhanced media awareness of genetic cancer motivates patients, including other patient groups. A higher number of participants, including more men, are attending GC due to the AJE. In terms of the rising complexity of genetic testing, the analysis of patients’ expectations and initiators for GC suggests that there is an urgent need to develop to participate motivation analysis. The factors revealed as impediments to accessing GC-HBOC guide recommendations to optimize access to genetic counseling. Medical educational programs for primary gynecologists and families at risk might be options to reach more participants.</p></div

Expectations of NFT counselees.

<p>Counselees quantified different expectations and motivational factors for visiting the Center for HBOC using a scale that ranged from 0 (motivation factor does not apply) to 4 (motivation factor applies completely).</p

Initiator groups for genetic counseling.

<p>Referral by <b>a)</b> medical professionals/physicians and <b>b)</b> Heidelberg University Hospital in the NFT and FT groups and the NFT subgroups “before AJ” and “after AJ”.</p

Characteristics of NFT counselees and influence of the “Angelina Jolie (AJ) effect” on them (“before AJ” and “after AJ” subgroups).

<p>Characteristics of NFT counselees and influence of the “Angelina Jolie (AJ) effect” on them (“before AJ” and “after AJ” subgroups).</p

Socio-demographic data of the entire study population (NFT and FT).

<p>Characteristics of all counselees and differences between the NFT and FT groups.</p