High frequency of MEFV disease-causing variants in children with very-early-onset inflammatory bowel disease.

BACKGROUND: Biological similarities between inflammatory bowel disease (IBD) and familial Mediterranean fever (FMF) have been described in humans and animal models suggesting a possible common genetic basis. FMF is caused by variants in the MEFV gene which encodes pyrin, an immune regulator. This study aimed to investigate the carrier rate of disease-causing MEFV variants in children of different ethnicities diagnosed with very-early-onset IBD (VEO-IBD). METHODS: The study included 23 children diagnosed with VEO-IBD who had undergone whole exome sequencing. The exomes were evaluated for MEFV monoallelic and biallelic disease-causing variants and compared to exome sequencing data of 250 probands with suspected monogenic diseases other than IBD. RESULTS: Of the 23 children diagnosed with VEO-IBD, 12 (52%) were carriers of at least one MEFV disease-causing variant, which was threefold higher than in individuals without IBD. The most frequent variants identified were p.M694V and p.E148Q (42% each). The allelic frequency of MEFV variants was found to be higher across the VEO-IBD group in 13 of 14 ethnicities compared to the control group. CONCLUSION: The study suggests that disease-causing variants in the MEFV gene should be sought in cases of VEO-IBD. However, the clinical importance of this finding is yet to be defined. IMPACT: There are biological similarities between inflammatory bowel disease and familial Mediterranean fever, suggesting a possible genetic relationship. Children less than 6 years old clinically diagnosed with inflammatory bowel disease have a threefold higher rate of disease-causing variants in the MEFV gene than controls. Monogenic testing in children with very-early-onset inflammatory bowel disease should include a search for MEFV variants.

Autosomal Recessive Rod-Cone Dystrophy with Mild Extra-Ocular Manifestations Due to a Splice-Affecting Variant in BBS9.

Bardet-Biedl syndrome (BBS), one of the most common forms of syndromic inherited retinal diseases (IRDs), is characterized by the combination of retinal degeneration with additional extra-ocular manifestations, including obesity, intellectual disability, kidney disease, polydactyly and other skeletal abnormalities. We observed an Israeli patient with autosomal recessive apparently non-syndromic rod-cone dystrophy (RCD). Extra-ocular findings were limited to epilepsy and dental problems. Genetic analysis with a single molecule molecular inversion probes-based panel that targets the exons and splice sites of 113 genes associated with retinitis pigmentosa and Leber congenital amaurosis revealed a homozygous rare missense variant in the BBS9 gene (c.263C>T;p.(Ser88Leu)). This variant, which affects a highly conserved amino acid, is also located in the last base of Exon 3, and predicted to be splice-altering. An in vitro minigene splice assay demonstrated that this variant leads to the partial aberrant splicing of Exon 3. Therefore, we suggest that this variant is likely hypomorphic. This is in agreement with the relatively mild phenotype observed in the patient. Hence, the findings in our study expand the phenotypic spectrum associated with BBS9 variants and indicate that variants in this gene should be considered not only in BBS patients but also in individuals with non-syndromic IRD or IRD with very mild extra-ocular manifestations.

A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies.

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.

[INHERITED COLORECTAL CANCER - UPDATED REVIEW].

INTRODUCTION: Significant progress has been achieved in recent years in the field of cancer genomics. The advancement in genomic technologies, molecular pathology and genetic testing, led to the discovery of novel genetic-hereditary factors, associated with colorectal cancer (CRC). There are currently ~20 identified genes that are linked to a higher risk of developing CRC; some of these genes are also linked to polyposis. The most prevalent hereditary syndrome to cause CRC is Lynch syndrome; its prevalence is believed to be 1:300 worldwide. Clinical data such as the age of onset, ancestry, number of polyps, histological features, molecular characteristics of the tumor and benign findings in other bodily systems, can be used to support the notion that the ailment is hereditary.

Possible biallelic inheritance in TIE1 in a family with congenital lymphedema, intestinal lymphangiectasia and cutis aplasia.

A short report of two male siblings born with cutis aplasia, lymphedema and intestinal lymphangiectasia, one found to carry bi-allelic variants in the TIE1 gene known to be associated with congenital lymphedema.

The Association between Preoperative Vitamin D Levels and Postoperative Complications in Patients Undergoing Colorectal Liver Metastasis Surgery.

(1) Background: Over the past several years, there has been a renewed interest with regard to the effect of pre-operative vitamin D levels on post-surgical outcomes. Pre-operative vitamin D deficiency has been associated with many negative post-operative outcomes. However, the role of vitamin D in postoperative outcomes in colorectal liver metastasis (CRLM) resection is relatively uninvestigated. Our study investigated the correlation between preoperative vitamin D levels and postoperative complications in patients undergoing resection for CRLM. (2) Methods: We retrospectively examined the post-operative course of 109 patients, who were evaluated based upon preoperative vitamin D levels: the first group had vitamin D levels less than 25 nmol/L (VIT D < 25 nmol/L) (n = 12) vs. the second group who had vitamin D levels equal to or greater than 25 nmol/L (VIT D ≥ 25 nmol/L) (n = 97). (3) Results: Patients with lower pre-operative vitamin D levels (VIT D < 25 nmol/L) had significantly higher rates of blood transfusions (33.3% vs. 10.3%, p = 0.01), post-operative surgical complications (50% vs. 17.5%, p = 0.009), and infectious complications (25% vs. 7.2%, p = 0.04). However, there was no difference in overall survival seen between the two groups. (4) Conclusions: The results of our study indicate that patients with preoperative vitamin D deficiency (defined as preoperative vitamin D levels less than 25 nmol/L) may have an increased risk of postoperative complications in patients undergoing liver surgery for metastatic colorectal cancer.

The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort.

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020-January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.

Crohn's Disease with Atypical Extra-Intestinal Manifestations Developing Under Treatment with Vedolizumab.

Crohn's disease is a chronic inflammatory bowel disease that can affect any part of the GI tract, which is frequently associated with extra-intestinal manifestations. Pulmonary parenchymal disease is very uncommon and usually considered to be debilitating and harder to diagnose. Pulmonary granulomas are rarely described in the literature as a complication of Crohn's disease. Here, we present a patient with Crohn's disease exacerbation who developed granulomatous lung disease under treatment with vedolizumab. Our case may add evidence to the emerging theory that gut-selective biologic agents could lead to upregulation of some pro-inflammatory factors leading to the evolution of pulmonary disease. LEARNING POINTS: Pulmonary parenchymal diseases are rare in Crohn's disease but they can be debilitating and life-threatening as they are usually tardily diagnosed; awareness of this association is of high value and could potentially shorten the time to a definite diagnosis.Pulmonary manifestations of Crohn's disease could be subclinical without any respiratory complaints and not diagnosed with conventional imaging modalities such as chest x-ray.Gut-selective biologic agents could lead to the emergence of extra-intestinal manifestations due to upregulation of multiple pro-inflammatory cytokines.