Familial Mediterranean fever (FMF) is an autosomal recessive disorder, particularly common in the Mediterranean area. Mutations in the MEVF gene cause it. AA Amyloidosis is the most severe complication of FMF leading to chronic renal failure. We describe a rare pediatric case of a phenotype I familial Mediterranean fever with V726A heterozygous mutation. The diagnosis was made at chronic kidney disease. We discuss through this case the importance of the early diagnosis of FMF heterozygous children which is not usually evident in some phenotypes. It will surely avoid fatal complications, inappropriate therapeutic approaches and higher healthcare costs.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

BACKGROUND: Recent in vitro studies using RB1+/- fibroblasts and MSCs have shown molecular and functional disruptions without the need for biallelic loss of RB1. However, this was not reflected in the recent in vitro studies employing RB1+/- retinal organoids. To gain further insights into the molecular disruptions in the RB1+/- retinal organoids, we performed a high throughput RNA sequencing analysis.
RESULTS: iPSCs were generated from RB1+/+ and RB1+/- OAMSCs derived from retinoblastoma patients. RB1+/+ and RB1+/- iPSCs were subjected to a step-wise retinal differentiation protocol. Retinal differentiation was evaluated by Real-time PCR and flow cytometry analysis of the retinal markers. To gain further insights into the molecular differences in RB1+/- retinal organoids, a high throughput RNA sequencing followed by differential gene expression analysis and gene set enrichment analysis (GSEA) was performed. The analysis revealed a shift from the regular metabolic process of glycolysis to oxidative phosphorylation in the RB1+/- retinal organoids. To investigate further, we performed assays to determine the levels of pyruvate, lactate and ATP in the retinal organoids. The results revealed significant increase in ATP and pyruvate levels in RB1+/- retinal organoids of day 120 compared to that of the RB1+/+. The results thus revealed enhanced ATP production in the RB1+/- retinal organoids.
CONCLUSIONS: The study provides novel insights into the metabolic phenotype of heterozygous RB1 mutant suggesting dysregulation of energy metabolism and glycolytic pathways to be first step even before the changes in cellular proliferation or other phenotypic consequences ensue.

BACKGROUND: Spondyloepimetaphyseal dysplasias (SEMD) are a large group of skeletal disorders represented by abnormalities of vertebrae in addition to epiphyseal and metaphyseal areas of bones. Several genes have been identified underlying different forms. ACAN gene mutations were found to cause Aggrecan-related bone disorders (spondyloepimetaphyseal dysplasias,spondyloepiphyseal dysplasias, familial osteochondritis dissecans and short stature syndromes). This study aims to find the disease causing variant in Egyptian patient with SEMD using whole exome sequencing.
METHODS: Whole-exome sequencing was performed for an Egyptian male patient who presented with short stature, clinical and radiological features suggestive of unclassified SEMD.
RESULTS: The study identified a novel de novo heterozygous ACAN gene variant (c.7378G>A; p.Gly2460Arg) in G3 domain. Mutations in ACAN gene have been more commonly associated with short stature than SEMD. The phenotype of our patient was intermediate in severity between spondyloepiphyseal dysplasia presentation; Kimberley type(SEDK) and Spondyloepimetaphyseal dysplasias Aggrecan (SEMDAG) CONCLUSIONS: Whole exome sequencing revealed a novel de novo ACAN gene variant in patient with SEDK. The clinical and skeletal phenotype of our patient was much severe than those reported originally and showed more metaphyseal involvement. To the best of our knowledge, two previous studies reported a heterozygous variant in ACAN with spondyloepiphyseal dysplasia presentation; Kimberley type.

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

OBJECTIVE: The ATM gene is one of the most common breast cancer (BC) susceptibility genes after BRCA1/2 and has been shown to be a moderate BC susceptibility gene. The association between ATM germline mutation and clinical features of BC is now unknown. In this article, clinicopathological features of BC patients with ATM germline heterozygous mutation were investigated.
METHODS: Patients admitted to the Medical Genetics department of a tertiary hospital between January 2020 and December 2022 were examined. Only invasive BC patients with pathogenic mutation, likely pathogenic mutation, or variants of uncertain significance (VUS) were included in the study.
RESULTS: In all, 121 patients were included in the study. The median age at the first cancer diagnosis of the patients was 44 years. Of the total number of patients, 75.2% (91) had the histological subtype of infiltrating ductal carcinoma, and 43% (52) had Luminal B molecular subtype features. At a median follow-up of 16 months, 5.8% (7) of patients developed cancer in the contralateral breast. In addition, 7.4% (9) of the patients developed a second primary cancer during follow-up. When the patients were compared according to ATM variant classification, the localization, histologic types, and molecular subtypes of the BC were not different between all groups (respectively; p=0.68, p=0.65, p=0.32).
CONCLUSIONS: To the best of our knowledge, this is the first publication that evaluates the clinical and pathological characteristics of BC patients with germline heterozygous ATM mutations in the Turkish population. When patients were compared according to variant classifications of ATM mutation, patients\' histological and molecular subtypes were similar.

OBJECTIVE: Factor 2 and Factor 5 mutations are among the most common procoagulant genetic disorders and are routinely evaluated in donor preparation. Homozygous mutations are contraindicated for surgery, but heterozygous mutations cannot be said to be an impediment. We aimed to investigate the effect of heterozygous gene mutation of F2 and/or F5 on complications.
METHODS: In our study, 210 living liver donors were examined. The available data of Factor 2 and 5 heterozygous positive donors were evaluated in terms of 21 donor patients and 30 liver recipients. The heterozygous positive group and the control group were statistically compared in terms of age, gender, length of hospital stay, post-operative deep vein thrombosis, pulmonary embolism, portal vein thrombosis, bile duct stenosis and bile leakage complications, lung infection and atelectasis, and wound infection. In addition, these patients were statistically compared in terms of laboratory tests. In addition, complications in recipients implanted with mutant grafts were evaluated statistically and numerically.
RESULTS: Hospital staying was longer statistically in the donor group with heterozygous mutations than in the control group. Hemoglobin and albumin blood levels were lower (p=0.031, p=0.016); INR and ALT levels were higher (p=0.005, p=0.047) statistically in the control group than in the donor group with heterozygous mutations. There was no statistically significant difference between heterozygous mutant groups in terms of biliary tract complications and hepatic vessel thrombosis in recipients.
CONCLUSIONS: Considering the longer hospital stay in the presence of these mutations, the increased need for treatment in this process and the close follow-up of liver functions should be considered.

Barth syndrome (BTHS) is caused by mutations in tafazzin resulting in deficits in cardiolipin remodeling that alter major metabolic processes. The tafazzin gene is encoded on the X chromosome, and therefore BTHS primarily affects males. Female carriers are typically considered asymptomatic, but age-related changes have been reported in female carriers of other X-linked disorders. Therefore, we examined the phenotype of female mice heterozygous for deletion of the tafazzin gene (Taz-HET) at 3 and 12 months of age. Food intakes, body masses, lean tissue and adipose depot weights, daily activity levels, metabolic measures, and exercise capacity were assessed. Age-related changes in mice resulted in small but significant genotype-specific differences in Taz-HET mice compared with their female Wt littermates. By 12 months, Taz-HET mice weighed less than Wt controls and had smaller gonadal, retroperitoneal, and brown adipose depots and liver and brain masses, despite similar food consumption. Daily movement, respiratory exchange ratio, and total energy expenditure did not vary significantly between the age-matched genotypes. Taz-HET mice displayed improved glucose tolerance and insulin sensitivity at 12 months compared with their Wt littermates but had evidence of slightly reduced exercise capacity. Tafazzin mRNA levels were significantly reduced in the cardiac muscle of 12-month-old Taz-HET mice, which was associated with minor but significant alterations in the heart cardiolipin profile. This work is the first to report the characterization of a model of female carriers of heterozygous tafazzin deficiency and suggests that additional study, particularly with advancing age, is warranted.

The agronomic potential of glutamate dehydrogenase 2 (GDH2) in maize kernel production was investigated by examining the impact of a mutation on the corresponding gene. Mu-insertion homozygous and heterozygous mutant lines lacking GDH2 activity were isolated and characterized at the biochemical, physiological and agronomic levels. In comparison to the wild type and to the homozygous ghd2 mutants, the heterozygous gdh2 mutant plants were characterized by a decrease in the root amino acid content, whereas in the leaves an increase of a number of phenolic compounds was observed. On average, a 30 to 40% increase in kernel yield was obtained only in the heterozygous gdh2 mutant lines when plants were grown in the field over two years. The importance of GDH2 in the control of plant productivity is discussed in relation to the physiological impact of the mutation on amino acid content, with primary carbon metabolism mostly occurring in the roots and secondary metabolism occurring in the leaves.