The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.

Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic ß-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype-phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context.

Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants.

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics.

Pediatric Acute Lymphoblastic Leukemia Emerging Therapies-From Pathway to Target.

Over the past 40 years, the 5-years-overall survival rate of pediatric cancer reached 75-80%, and for acute lymphoblastic leukemia (ALL), exceeded 90%. Leukemia continues to be a major cause of mortality and morbidity for specific patient populations, including infants, adolescents, and patients with high-risk genetic abnormalities. The future of leukemia treatment needs to count better on molecular therapies as well as immune and cellular therapy. Advances in the scientific interface have led naturally to advances in the treatment of childhood cancer. These discoveries have involved the recognition of the importance of chromosomal abnormalities, the amplification of the oncogenes, the aberration of tumor suppressor genes, as well as the dysregulation of cellular signaling and cell cycle control. Lately, novel therapies that have already proven efficient on relapsed/refractory ALL in adults are being evaluated in clinical trials for young patients. Tirosine kinase inhibitors are, by now, part of the standardized treatment of Ph+ALL pediatric patients, and Blinatumomab, with promising results in clinical trials, received both FDA and EMA approval for use in children. Moreover, other targeted therapies such as aurora-kinase inhibitors, MEK-inhibitors, and proteasome-inhibitors are involved in clinical trials that include pediatric patients. This is an overview of the novel leukemia therapies that have been developed starting from the molecular discoveries and those that have been applied in pediatric populations.

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome.

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene (FMR1) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice.

Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

Towards Multifractality through an Ernst-Type Potential in Complex Systems Dynamics.

Some possible correspondences between the Scale Relativity Theory and the Space-Time Theory can be established. Since both the multifractal Schrödinger equation from the Scale Relativity Theory and the General Relativity equations for a gravitational field with axial symmetry accept the same SL(2R)-type invariance, an Ernst-type potential (from General Relativity) and also a multi-fractal tensor (from Scale Relativity) are highlighted in the description of complex systems dynamics. In this way, a non-differentiable description of complex systems dynamics can become functional, even in the case of standard theories (General Relativity and Quantum Mechanics).

Coherences in the Dynamics of Physical Systems from a Multifractal Perspective of Motion.

Using an analogy between the multi-fractal Schrödinger equation and the dumped oscillator equation through a special ansatz, Stoler-type coherences in the dynamics of physical systems are highlighted. Such a result implies a Ricatti-type gauge, a process that can be considered a calibration of the difference between the kinetic and potential energy of a Lagrangian, specified as a perfect square in generic coordinates.

Implications and Consequences of SL(2R) as Invariance Group in the Description of Complex Systems Dynamics from a Multifractal Perspective of Motion.

Possible implications and consequences of using SL(2R) as invariance groups in the description at any scale resolution of the dynamics of any complex system are analyzed. From this perspective and based on Jaynes' remark (any circumstance left unspecified in the description of any complex system dynamics has the concrete expression in the existence of an invariance group), in the present paper one specifies such unspecified circumstances that result directly from the consideration of the canonical formalism induced by the SL(2R) as invariance group. It follows that both the Hamiltonian function and the Guassian distribution acquire the status of invariant group functions, the parameters that define the Hamiltonian acquire statistical significances based on a principle of maximizing informational energy, the class of statistical hypotheses specific to Gaussians of the same average acts as transitivity manifolds of the group (transitivity manifolds which can be correlated with the multifractal-non-multifractal scale transitions), joint invariant functions induced through SL(2R) groups isomorphism (the SL(2R) variables group, and the SL(2R) parameters group, etc.). For an ensemble of oscillators of the same frequency, the unspecified circumstances return to the ignorance of the amplitude and phase of each of the oscillators, which forces the recourse to a statistical ensemble traversed by the transformations of the Barbilian-type group. Finally, the model is validated based on numerical simulations and experimental results that refer to transient phenomena in ablation plasmas. The novelty of our model resides in the fact that fractalization through stochasticization is imposed through group invariance, situation in which the group's transitivity manifolds can be correlated with the scale resolution.

The Role of Information in Managing Interactions from a Multifractal Perspective.

In the framework of the multifractal hydrodynamic model, the correlations informational entropy-cross-entropy manages attractive and repulsive interactions through a multifractal specific potential. The classical dynamics associated with them imply Hubble-type effects, Galilei-type effects, and dependences of interaction constants with multifractal degrees at various scale resolutions, while the insertion of the relativistic amendments in the same dynamics imply multifractal transformations of a generalized Lorentz-type, multifractal metrics invariant to these transformations, and an estimation of the dimension of the multifractal Universe. In such a context, some correspondences with standard cosmologies are analyzed. Since the same types of interactions can also be obtained as harmonics mapping between the usual space and the hyperbolic plane, two measures with uniform and non-uniform temporal flows become functional, temporal measures analogous with Milne's temporal measures in a more general manner. This work furthers the analysis published recently by our group in "Towards Interactions through Information in a Multifractal Paradigm".

Multifractality through Non-Markovian Stochastic Processes in the Scale Relativity Theory. Acute Arterial Occlusions as Scale Transitions.

By assimilating biological systems, both structural and functional, into multifractal objects, their behavior can be described in the framework of the scale relativity theory, in any of its forms (standard form in Nottale's sense and/or the form of the multifractal theory of motion). By operating in the context of the multifractal theory of motion, based on multifractalization through non-Markovian stochastic processes, the main results of Nottale's theory can be generalized (specific momentum conservation laws, both at differentiable and non-differentiable resolution scales, specific momentum conservation law associated with the differentiable-non-differentiable scale transition, etc.). In such a context, all results are explicated through analyzing biological processes, such as acute arterial occlusions as scale transitions. Thus, we show through a biophysical multifractal model that the blocking of the lumen of a healthy artery can happen as a result of the "stopping effect" associated with the differentiable-non-differentiable scale transition. We consider that blood entities move on continuous but non-differentiable (multifractal) curves. We determine the biophysical parameters that characterize the blood flow as a Bingham-type rheological fluid through a normal arterial structure assimilated with a horizontal "pipe" with circular symmetry. Our model has been validated based on experimental clinical data.

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

Simulated and measured piezoelectric energy harvesting of dynamic load in tires.

From 2007 in US and from 2022 in EU it is mandatory to use TPMS monitoring in new cars. Sensors mounted in tires require a continuous power supply, which currently only is from batteries. Piezoelectric energy harvesting is a promising technology to harvest energy from tire movement and deformation to prolong usage of batteries and even avoid them inside tires. This study presents a simpler method to simultaneous model the tire deformation and piezoelectric harvester performance by using a new simulation approach - dynamic bending zone. For this, angular and initial velocities were used for rolling motion, while angled polarization was introduced in the model for the piezoelectric material to generate correct voltage from tire deformation. We combined this numerical simulation in COMSOL Multiphysics with real-life measurements of electrical output of a piezoelectric energy harvester that was mounted onto a tire. This modelling approach allowed for 10 times decrease in simulation time as well as simpler investigation of systems parameters influencing the output power. By using experimental data, the simulation could be fine-tuned for material properties and for easier extrapolation of tire deformation with output harvested energy from simulations done at low velocity to the high velocity experimental data.

Genotype-Phenotype Correlations in 2q37-Deletion Syndrome: An Update of the Clinical Spectrum and Literature Review.

2q37 microdeletion/deletion syndrome (2q37DS) is one of the most common subtelomeric deletion disorders, caused by a 2q37 deletion of variable size. The syndrome is characterized by a broad and diverse spectrum of clinical findings: characteristic facial dysmorphism, developmental delay/intellectual disability (ID), brachydactyly type E, short stature, obesity, hypotonia in infancy, and abnormal behavior with autism spectrum disorder. Although numerous cases have been described so far, the exact mapping of the genotype and phenotype have not yet been achieved. MATERIALS AND METHODS: In this study we analyzed nine newly diagnosed cases with 2q37 deletion (3 male/6 female, aged between 2 and 30 years old), and followed up at the Iasi Regional Medical Genetics Centre. All patients were tested first with MLPA using combined kits P036/P070 subtelomeric screening mix and follow-up mix P264; after, the deletion size and location were confirmed via CGH-array. We compared our findings with the data of other cases reported in the literature. RESULTS: From nine cases, four had pure 2q37 deletions of variable sizes, and five presented deletion/duplication rearrangements (with chromosomes 2q, 9q, and 11p). In most cases, characteristic phenotypic aspects were observed: 9/9 facial dysmorphism, 8/9 global developmental delay and ID, 6/9 hypotonia, 5/9 behavior disorders, and 8/9 skeletal anomalies-especially brachydactyly type E. Two cases had obesity, one case had craniosynostosis, and four had heart defects. Other features found in our cases included translucent skin and telangiectasias (6/9), and a hump of fat on the upper thorax (5/9). CONCLUSIONS: Our study enriches the literature data by describing new clinical features associated with 2q37 deletion, and possible genotype-phenotype correlations.

Combined flow cytometry natural killer immunophenotyping and KIR/HLA-C genotyping reveal remarkable differences in acute myeloid leukemia patients, but suggest an overall impairment of the natural killer response.

Introduction: Natural killer (NK) cells are key anti-tumor effectors of the innate immunity. Phenotypic differences allow us to discriminate in between three functional stages of maturation, named immature, mature and hypermature that are distinctive in terms of receptor expression, cytokine secretion, cytotoxic properties and organ trafficking. NKs display an impressive repertoire of highly polymorphic germline encoded receptors that can be either activating, triggering the effector's function, or inhibitory, limiting the immune response. In our study, we have investigated peripheral blood NK cells of acute myeloid leukemia (AML) patients. Methods: The Killer Immunoglobulin-like receptors (KIRs) and the HLA-C genotypes were assessed, as HLA-C molecules are cognate antigens for inhibitory KIRs. Results: The AA mainly inhibitory KIR haplotype was found in a higher proportion in AML, while a striking low frequency of the 2DS3 characterized the mainly activating Bx haplotype. Flow cytometry immunophenotyping evidenced a lower overall count of NK cells in AML versus healthy controls, with lower percentages of the immature and mature subpopulations, but with a markedly increase of the hypermature NKs. The analysis of the KIR2DL1, KIR2DL2, KIR2DL3, KIR3DL1, and NKG2A inhibitory receptors surface expression revealed a remarkable heterogeneity. However, an overall trend for a higher expression in AML patients could be noticed in all maturation subpopulations. Some of the AML patients with complex karyotypes or displaying a FLT3 gene mutation proved to be extreme outliers in terms of NK cells percentages or inhibitory receptors expression. Discussion: We conclude that while the genetic background investigation in AML offers important pieces of information regarding susceptibility to disease or prognosis, it is flow cytometry that is able to offer details of finesse in terms of NK numbers and phenotypes, necessary for an adequate individual evaluation of these patients.

Association between Eating Patterns and Quality of Life in Patients with Familial Hypercholesterolemia.

(1) Background: Familial hypercholesterolemia (FH) is a genetic disease that has autosomal dominant inheritance, being characterized by increased levels of low-density lipoproteins (LDLs) due to a decreased clearance of the circulant LDLs. Alimentation is a key factor in patients with FH. Implementing a restrictive diet may have a significant impact on their quality of life, besides the social and environmental factors. (2) Methods: We realized a prospective study that was conducted in the Cardiovascular Rehabilitation Clinic from the Clinical Rehabilitation Hospital and that included 70 patients with FH and 20 controls (adults with no comorbidities). We evaluated their lipid profile, their quality of life through the Short Form-36 Questionnaire, and their eating habits. (3) Results: Lower scores in the quality-of-life questionnaire were obtained in the FH group both in the case of the physical (73.06 vs. 87.62) and the mental component (75.95 vs. 83.10). Women had better physical function (85 vs. 75) and physical role than men (100 vs. 75). The group aged over 65 has the score lowest for all 10 components. Overeating was driven by boredom and was more frequent on weekends in the FH group. None of the patients in the control group felt loneliness or depression associated with overeating. (4) Conclusions: Overeating in patients with FH is associated with a lower quality of life. The complexity of these patients needs a multidisciplinary approach. Thus, the quality-of-life questionnaire should be implemented in their periodic follow-ups in order to increase their general status, paying special attention to geriatric patients.

ORPHAcodes use for the coding of rare diseases: comparison of the accuracy and cross country comparability.

BACKGROUND: Estimates of rare disease (RD) population impact in terms of number of affected patients and accurate disease definition is hampered by their under-representation in current coding systems. This study tested the use of a specific RD codification system (ORPHAcodes) in five European countries/regions (Czech Republic, Malta, Romania, Spain, Veneto region-Italy) across different data sources over the period January 2019-September 2021. RESULTS: Overall, 3133 ORPHAcodes were used to describe RD diagnoses, mainly corresponding to the disease/subtype of disease aggregation level of the Orphanet classification (82.2%). More than half of the ORPHAcodes (53.6%) described diseases having a very low prevalence (< 1 case per million), and most commonly captured rare developmental defects during embryogenesis (31.3%) and rare neurological diseases (17.6%). ORPHAcodes described disease entities more precisely than corresponding ICD-10 codes in 83.4% of cases. CONCLUSIONS: ORPHAcodes were found to be a versatile resource for the coding of RD, able to assure easiness of use and inter-country comparability across population and hospital databases. Future research on the impact of ORPHAcoding as to the impact of numbers of RD patients with improved coding in health information systems is needed to inform on the real magnitude of this public health issue.

Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN.

Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP-related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP-inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.

High magnetoelectric coupling of Metglas and P(VDF-TrFE) laminates.

Magnetoelectric (magnetic/piezoelectric) heterostructures bring new functionalities to develop novel transducer devices such as (wireless) sensors or energy harvesters and thus have been attracting research interest in the last years. We have studied the magnetoelectric coupling between Metglas films (2826 MB) and poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) in a laminate structure. The metallic Metglas film itself served as bottom electrode and as top electrode we used an electrically conductive polymer, poly(3,4-ethylene-dioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). Besides a direct electrical wiring via a graphite ink, a novel contactless readout method is presented using a capacitive coupling between the PEDOT:PSS layer and an electrode not in contact with the PEDOT:PSS layer. From the experimental result we determined a magnetoelectric coupling of 1445 V/(cm·Oe) at the magnetoelastic resonance of the structure, which is among the highest reported values for laminate structures of a magnetostrictive and a piezoelectric polymer layer. With the noncontact readout method, a magnetoelectric coupling of about 950 V/(cm·Oe) could be achieved, which surpasses previously reported values for the case of direct sample contacting. 2D laser Doppler vibrometer measurements in combination with FE simulations were applied to reveal the complex vibration pattern resulting in the strong resonant response.

Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype-Phenotype Correlation.

The most frequent microdeletion, 22q11.2 deletion syndrome (22q11.2DS), has a wide and variable phenotype that causes difficulties in diagnosis. 22q11.2DS is a contiguous gene syndrome, but due to the existence of several low-copy-number repeat sequences (LCR) it displays a high variety of deletion types: typical deletions LCR A-D-the most common (~90%), proximal deletions LCR A-B, central deletions (LCR B, C-D) and distal deletions (LCR D-E, F). METHODS: We conducted a retrospective study of 59 22q11.2SD cases, with the aim of highlighting phenotype-genotype correlations. All cases were tested using MLPA combined kits: SALSA MLPA KIT P245 and P250 (MRC Holland). RESULTS: most cases (76%) presented classic deletion LCR A-D with various severity and phenotypic findings. A total of 14 atypical new deletions were identified: 2 proximal deletions LCR A-B, 1 CES (Cat Eye Syndrome region) to LCR B deletion, 4 nested deletions LCR B-D and 1 LCR C-D, 3 LCR A-E deletions, 1 LCR D-E, and 2 small single gene deletions: delDGCR8 and delTOP3B. CONCLUSIONS: This study emphasizes the wide phenotypic variety and incomplete penetrance of 22q11.2DS. Our findings contribute to the genotype-phenotype data regarding different types of 22q11.2 deletions and illustrate the usefulness of MLPA combined kits in 22q11.2DS diagnosis.

Genetic Polymorphisms in a Familial Hypercholesterolemia Population from North-Eastern Europe.

(1) Background: Familial hypercholesterolemia (FH) is one of the most prevalent inherited metabolic disorders. The purpose of the study was to investigate the role in cardiovascular disease (CVD) of PAI-1, ACE, ApoB-100, MTHFR A1298C, and C677T. (2) Methods: From a group of 1499 patients, we included 52 patients diagnosed with FH phenotype and 17 patients in a control group. (3) Results: Most of the FH patients had multiple comorbidities compared to the control group, such as atherosclerosis (48.1% vs. 17.6%), atherosclerotic cardiovascular disease (ASCVD 32.7% vs. 11.8%), and metabolic syndrome (MetS, 40.4% vs. 11.8%). In total, 66.7% of the FH patients had PAI-1 4G/5G genotype and MetS. Between 4G/5G and 4G/4G, a statistically significant difference was observed (p = 0.013). FH patients with ApoB R3500Q polymorphism were correlated with ASCVD (p = 0.031). Both MTHFR C677T and A1298C polymorphisms had a significant correlation with gender, alcohol consumption, and smoking status. ACE polymorphism was associated with ATS in FH patients, statistically significant differences being observed between heterozygous and homozygous D genotype (p = 0.036) as well as between heterozygous and homozygous I genotype (p = 0.021). (4) Conclusions: A link between these polymorphisms was demonstrated in the FH group for ATS, ASCVD, and MetS.