This review explores how precision medicine is transforming the diagnosis, classification, and treatment of cardiomyopathies. It focuses on the integration of genetic profiling, biomarkers, and imaging to deliver more ta...This review explores how precision medicine is transforming the diagnosis, classification, and treatment of cardiomyopathies. It focuses on the integration of genetic profiling, biomarkers, and imaging to deliver more tailored and effective care. We review major cardiomyopathy subtypes: hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular, with a focus on genetic drivers, including mitochondrial mutations. Pediatric forms are discussed in the context of syndromic and non-syndromic differences. We highlight the clinical value of combining biomarkers (molecular and serological) with imaging modalities, such as echocardiography, for better risk stratification, especially in predicting sudden cardiac death. The utility of animal models in translating genetic findings into disease understanding is also emphasized. Finally, we touch on innovations like genome editing, gene therapies, and pharmacogenomics for personalized treatment. Precision medicine offers a promising future for cardiomyopathy care. By targeting the underlying causes and tailoring treatment to each patient's genetic and molecular profile, we can achieve more accurate diagnoses, better risk prediction, and improved outcomes, bringing us closer to truly individualized cardiovascular care.
This study investigated genetic causes of 46, XY DSD in 134 Chinese patients via whole-exome sequencing (WES). Clinical data analysis identified 86 rare variants (14 novel, 72 recurrent) across 46, XY DSD-related genes....This study investigated genetic causes of 46, XY DSD in 134 Chinese patients via whole-exome sequencing (WES). Clinical data analysis identified 86 rare variants (14 novel, 72 recurrent) across 46, XY DSD-related genes. Following ACMG guidelines, 71 variants were classified as pathogenic/likely pathogenic (P/LP). Affected genes were linked to androgen production/function (63 variants), testicular development (19), and syndromic forms (4). SRD5A2, AR, and NR5A1 emerged as the most frequent causative genes, accounting for ~90% of cases. Novel variants in 11 genes expanded the genetic spectrum, offering insights into underlying mechanisms and improving diagnostic precision. These findings enhance understanding of 46, XY DSD pathogenesis and underscore WES's utility in resolving diagnostic challenges for improved clinical management.
Autosomal recessive polycystic kidney disease (ARPKD) is a rare but severe hereditary renal disorder characterized by bilaterally enlarged, cystic kidneys and varying degrees of hepatic fibrosis, often leading to early-o...Autosomal recessive polycystic kidney disease (ARPKD) is a rare but severe hereditary renal disorder characterized by bilaterally enlarged, cystic kidneys and varying degrees of hepatic fibrosis, often leading to early-onset kidney failure and significant morbidity. While most ARPKD cases are linked to mutations in the PKHD1 gene, recent advances in genomic sequencing have revealed that mutations in other genes, including PDIA6, may contribute to similar phenotypes. The PDIA6 gene encodes protein disulfide isomerase A6, which plays a critical role in protein folding within the endoplasmic reticulum (ER) and in the regulation of ER stress responses. Here, we report a rare and complex case of a full-term male neonate born to consanguineous Syrian refugee parents, who presented with a clinical constellation of features including polycystic kidney disease, severe oligohydramnios, pulmonary hypoplasia, microcephaly, rib thoracic dysplasia, and global developmental delay. Genetic analysis using whole-exome sequencing identified a homozygous two-base deletion in exon 5 of the PDIA6, resulting in a premature stop codon. Early diagnosis via genomic tools is essential for prognosis, management, and genetic counseling.
Monogenic Diabetes Mellitus refers to heterogeneous forms of diabetes mellitus (DM) caused by a single gene pathogenic variant. Neurodevelopmental disorders (NDDs) are clinically and molecularly heterogeneous conditions...Monogenic Diabetes Mellitus refers to heterogeneous forms of diabetes mellitus (DM) caused by a single gene pathogenic variant. Neurodevelopmental disorders (NDDs) are clinically and molecularly heterogeneous conditions characterized by an impairment of the nervous system development and/or function, with a wide clinical spectrum of variability. Over the last decade, Next Generation Sequencing (NGS) approaches have played a crucial role in the discovery of many monogenic causes underlying both NDDs and diabetes. In this systematic review, we aim to overview novel and emerging monogenic diseases presenting with pediatric diabetes and concomitant NDDs. The literature search was run in PubMed and Embase with a set of appropriate keywords. We examined 26 articles. Pathogenic variants have been classified according to the age of diabetes onset. In-depth analysis has been conducted for the selected papers, focusing on clinical description and molecular implications for a definite disease-causing gene. Interesting papers have revealed in recent years the occurrence of potential shared disease mechanisms underlying glucose and insulin metabolism and brain development and function. The broad clinical and molecular spectrum of DM-associated NDDs highlights the importance of a comprehensive and multidisciplinary management of these emerging clinical conditions and the increasingly crucial role of appropriate therapeutic approaches.
An adult with kidney failure had compound-heterozygous TMEM126B variants causing mitochondrial complex I deficiency. This expands TMEM126B to mitochondrial nephropathy and supports including mitochondrial genes in renal...An adult with kidney failure had compound-heterozygous TMEM126B variants causing mitochondrial complex I deficiency. This expands TMEM126B to mitochondrial nephropathy and supports including mitochondrial genes in renal genetic testing.
Neurodevelopmental disorders (NDD) are a group of complex conditions characterized by marked phenotypic heterogeneity, primarily involving impairments in cognitive, emotional, and motor development. Approximately 40%-60%...Neurodevelopmental disorders (NDD) are a group of complex conditions characterized by marked phenotypic heterogeneity, primarily involving impairments in cognitive, emotional, and motor development. Approximately 40%-60% of patients with rare NDD remain genetically undiagnosed. Recently, RNU2-2 and RNU5B-1 have been identified as novel genes underlying the "RNUopathies" a syndromic NDD caused by variants in non-coding spliceosomal genes. In this study, we aimed to focus on RNU2-2 and RNU5B-1 by analyzing the whole-genome sequencing (WGS) data from 18326 Chinese individuals (including 2970 trios and 9416 samples without parental data), among whom 4900 had confirmed NDD phenotypes. Reanalysis of WGS data solved the previously undiagnosed cases of four patients with NDD carrying de novo variants in RNU genes, including three patients carrying the RNU2-2 variants (two cases with n.4G>A and one case with n.35A>G), and one case with an unreported RNU5B-1 variant (n.38C>T). In this study, detailed phenotypic elaboration and comparison with previous studies help clinicians in more effective diagnosis of NDD and underscore the importance of reanalyzing negative genetic data, which deepens our understanding of the "RNUopathies."
The study aimed to report genotype-phenotype correlation in children with cystic fibrosis. This prospective multicentric study was done at four centres. Variants were tested for two common variants, followed by exome seq...The study aimed to report genotype-phenotype correlation in children with cystic fibrosis. This prospective multicentric study was done at four centres. Variants were tested for two common variants, followed by exome sequencing using NGS. Patients with cystic fibrosis who have one or more pathogenic/likely pathogenic variants were included in this study. The study included 260 children. Boys were more common (70.6% vs. 55.3%), and consanguinity was more prevalent (31.7% vs. 14.2%) in patients with non-c.1520_1522del variants. The 3849+10kbC>T variant had less pancreatic insufficiency, a higher age at diagnosis, and lower sweat chloride values compared to the c.1520_1522del variant. The median (IQR) age at diagnosis was significantly lower [1.5 (0.5, 7) vs. 4 (1.1, 9.4 years)], and pancreatic insufficiency (80.4% vs. 66.4%) and consanguinity (44% vs. 7.1%) were significantly more frequent in patients with homozygous variants compared to compound heterozygous variants. There was no difference in the proportion of Pseudomonas or Staphylococcus colonisation, spirometry parameters or frequency of bronchiectasis amongst various genetic groups. To conclude, the proportion of boys and consanguinity was higher with non-c.1520_1522del variants. The 3849+10kbC>T variant exhibited some peculiar phenotypic features. The patients with homozygous variants were younger at diagnosis and had higher pancreatic insufficiency.
Studies from the subcontinent on the utility of Whole Exome Sequencing (WES) in electro-clinical phenotypes of childhood-onset drug-resistant epilepsy (DRE) syndromes, particularly the developmental and epileptic encepha...Studies from the subcontinent on the utility of Whole Exome Sequencing (WES) in electro-clinical phenotypes of childhood-onset drug-resistant epilepsy (DRE) syndromes, particularly the developmental and epileptic encephalopathies (DEE), are rare in the literature. Patients with DRE phenotypes of presumed genetic etiology with an age of onset of epilepsy < 12 years, with/without developmental encephalopathy, were included in this study. Our study cohort (N = 175) included 158 trios, 6 duos, and 11 proband-only samples. Age at onset of seizures was ≤ 3 years in 76.6% and > 3 years in 23.4%, with developmental delay noted in 80.6% of the cohort. The overall yield of pathogenic/likely pathogenic variants in WES was 38.9% (68/175, 19 were novel); for trio-WES it was 41.1%. Predominantly de novo variants accounted for 45 out of 68 cases (66.2%), and the most frequent disease-causing variants were missense (74%). Younger age at onset of epilepsy, female gender and electroclinical diagnosis of Dravet syndrome were associated with a higher yield as opposed to focal epilepsies. Precision medicine was considered tenable in 25/68 (36.8%) cases. Our study reveals a significant yield of trio-WES for de novo variants in childhood-onset DRE/DEE. Female gender, early age at onset, and specific electro-clinical phenotypes have a higher likelihood of identifying a monogenic etiology.
Mediator of DNA damage checkpoint 1 (MDC1) is a protein closely associated with the repair of DNA damage. Recently, we identified three novel variants (NM_014641.3:c.C5977T; p.R1993X) (NM_014641.3:c.C5644T; p.R1882X; c.A...Mediator of DNA damage checkpoint 1 (MDC1) is a protein closely associated with the repair of DNA damage. Recently, we identified three novel variants (NM_014641.3:c.C5977T; p.R1993X) (NM_014641.3:c.C5644T; p.R1882X; c.A1T; p.M1L) in MDC1 in two patients with severe oligoasthenoteratozoospermia (OAT). In vitro validation showed that the p.R1882X variant resulted in the truncation of the MDC1 protein, and the p.R1993X variant resulted in the degradation of the MDC1 protein after truncation. Immunofluorescence demonstrated that the truncated protein caused by the variants affected the colocalization relationship between MDC1 and its interacting protein γH2AX. Additionally, one of the patients and his wife underwent intracytoplasmic sperm injection (ICSI), but the result was unsatisfactory. We screened out the variants of MDC1 in patients with OAT for the first time, and this research could afford precise genetic diagnosis for the patients. It has broadened the variant spectrum of MDC1 , which is conducive to the development of targeted therapeutic strategies.
Zgheib O, Rio Frio T, Pellegrinelli JM
… +10 more, Gimelli S, Marconi C, Le Mercier D, Rebollo Polo M, Habre C, Fluss J, Ha-Vinh Leuchter R, Abramowicz M, Giannini R, Fokstuen S
The Male-Specific Lethal 2 Homolog (MSL2) gene was recently reported to be responsible for a novel, rather severe neurodevelopmental syndrome including brain abnormalities. We report the first prenatal case of an MSL2-re...The Male-Specific Lethal 2 Homolog (MSL2) gene was recently reported to be responsible for a novel, rather severe neurodevelopmental syndrome including brain abnormalities. We report the first prenatal case of an MSL2-related pathology caused by a de novo MSL2 splice variant (c.142+1G>T). RNA study on amniotic fluid cells showed an intronic inclusion and frameshift, consistent with loss-of-function intolerance. The fetus, who presented with bilateral moderate ventriculomegaly, also carried a paternally inherited 15q13 microduplication. Brain MRI at 2 and 4 months of age showed stable, mildly enlarged lateral ventricles. Clinical evaluation at 11 months revealed only a mild developmental delay. This case illustrates the challenges in predicting the postnatal outcome of recently characterized syndromes with limited documented cases, especially in association with a second independent genetic anomaly. Follow-up will be crucial to better define the developmental impact of this first reported MSL2 splice mutation in combination with the 15q13 microduplication, and characterization of more patients with MSL2 mutations will contribute to expanding the phenotypic spectrum.
Zabihi R, Zamani M, Chamanrou N
… +19 more, Zeighami J, Seifi T, Ashoori S, Parvas S, Yadegari T, Mousavi F, Khajevandian E, Sarvari M, Shojaei K, Nourbakhsh P, Keikhaei B, Aminzadeh M, Ahmadi R, Anaei MM, Sedaghat A, Saberi A, Hamid M, Shariati G, Galehdari H
Genetic skeletal disorders (GSDs) comprise a diverse group of disorders that affect bone development and homeostasis. In some areas of Iran, GSD occurs more frequently than in other places for still unknown reasons. The...Genetic skeletal disorders (GSDs) comprise a diverse group of disorders that affect bone development and homeostasis. In some areas of Iran, GSD occurs more frequently than in other places for still unknown reasons. The aim of this study was to characterize the genetic landscape of GSDs in a cohort from southwestern Iran using Exome sequencing (ES), with a focus on identifying pathogenic and likely pathogenic variants. Osteogenesis Imperfecta (OI) was the most prevalent disorder, with an unexpectedly high frequency of autosomal recessive subtypes, likely due to a high consanguinity rate (61.3%) in the cohort. Achondroplasia (ACH) was the second most common disease and, comparable to another population, the NM_000142.5:c.1138G>A, p.(Gly380Arg), was the most common variant in FGFR3. ES identified twenty novel and fifteen previously reported pathogenic variants in several genes associated with GSDs. We provide the first comprehensive ES-based molecular diagnosis of GSDs in an Iranian population and uncover novel pathogenic variants that expand the known spectrum of variants. The results underscore the importance of genetic testing in the diagnosis of rare skeletal diseases and highlight the need for targeted genetic counseling in populations with high consanguinity.
Young RE, Qiao L, Hernan R
… +36 more, Sweetser DA, Waxler JL, Scott DA, Scott TM, Lalani SR, Azamian MS, Rosenfeld JA, Bostwick B, Burrage LC, Undiagnosed Diseases Network, Rodan LH, Russell BE, Dutra-Clarke M, Kruer M, Bakhtiarim S, Darvish H, Amor DJ, Rahman S, Stals K, Bradley L, Byrne S, Tolusso LK, Wong B, Benedict L, Wallis K, Micke K, Colson C, Smol T, Southwick SV, Miller KA, Kush ML, Chorin O, Rothschild A, Wang W, Shen Y, Chung WK
LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricu...LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.
Complete absence of symptoms in a mother carrying CAMTA1 c.1544C>A contrasts with severe congenital ataxia in her son. Early intervention at 16 months led to exceptional recovery (GMFM-88: 56.5% → 96%), demonstrating unp...Complete absence of symptoms in a mother carrying CAMTA1 c.1544C>A contrasts with severe congenital ataxia in her son. Early intervention at 16 months led to exceptional recovery (GMFM-88: 56.5% → 96%), demonstrating unprecedented intrafamilial variability and neuroplasticity potential in CAMTA1-related disorders.
Congenital microcoria (MCOR) is a rare inherited ocular disorder. Here, we describe a novel nonsense variant in the CPAMD8 gene in a patient with MCOR. We conducted a comprehensive clinical examination of a patient diagn...Congenital microcoria (MCOR) is a rare inherited ocular disorder. Here, we describe a novel nonsense variant in the CPAMD8 gene in a patient with MCOR. We conducted a comprehensive clinical examination of a patient diagnosed with MCOR and performed whole-exome sequencing to identify potential pathogenic variants. Additionally, bioinformatics prediction tools were employed to assess the impact of the identified variant on protein structure and function. The patient presented with hallmark features of MCOR, such as bilaterally constricted pupils and a poor response to mydriatic agents. A novel homozygous nonsense variant, c.2679C>G (p.Tyr893*), was identified in the CPAMD8 gene. Protein modeling revealed that the variant results in complete truncation of the C-terminal domain of CPAMD8, disrupting its functional domains and potentially affecting its biological activity. Furthermore, electrostatic potential energy analysis demonstrated increased surface asymmetry of the protein, suggesting that the variant may interfere with protein-molecule interactions. Previous studies have suggested a strong association between MCOR and deletions in the 13q32.1 region of chromosome 13; however, the specific pathogenic genes involved have remained unclear. In this study, we show that the nonsense variant c.2679C>G (p.Tyr893*) in CPAMD8 is associated with MCOR, providing new insights into the genetic basis of the disease.
Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, a...Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, and increased risk of metastasis and recurrence. Although no high penetrance predisposing gene has been identified at present, the estimated contribution of genetics is significant. Our study explored five families presenting FNMTC using Whole-Exome Sequencing and found three candidate genes: TELO2 in one family, UACA and BCL2L11 in another. All of these tumor suppressor genes are expressed in the thyroid, exhibit under-expression in tumor tissue compared to healthy tissue both in silico and in our samples, and two of them are known to be involved in thyroid carcinogenesis via the FOXO3A pathway. Functional analysis to validate these candidate genes in thyroid cancer cells showed that one of the three, BCL2L11, has a tumor suppressor effect on proliferation and apoptosis. Their impact on hereditary predisposition to thyroid cancer, as well as their combined effects, requires further study. Indeed, a case-control study would be essential to determine the diagnostic utility of their routine analysis.
Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium un...Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter. We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62). The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants, including c.355C>T; p.Arg119*, c.493 + 1G>A, c.508C>T; p.Gln170*, c.547C>T; p.Gln183*, c.1226C>G; p.Ser409*, and c.553C>T; p.Arg185*. Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases. A separate pedigree contained monozygotic twins who exhibited an indistinguishable clinical course, emphasizing the consistency of the genotype-driven phenotype. Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years. Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%). Functional studies targeting MCU modulation may provide future therapeutic options.
of clinical and molecular findings in patients with biallelic variants in PDCD6IP.of clinical and molecular findings in patients with biallelic variants in PDCD6IP.
We report the first known case of a 9-year-old male with early-onset epilepsy, syncope, and ictal asystole-requiring pacemaker implantation at the age of seven-associated with a pathogenic variant in FGF12.We report the first known case of a 9-year-old male with early-onset epilepsy, syncope, and ictal asystole-requiring pacemaker implantation at the age of seven-associated with a pathogenic variant in FGF12.
Autosomal recessive intellectual disability affects 1%-3% of the general population and is a major concern in countries where consanguineous marriages are common. Mental retardation autosomal recessive 48 (MRT 48) (OMIM...Autosomal recessive intellectual disability affects 1%-3% of the general population and is a major concern in countries where consanguineous marriages are common. Mental retardation autosomal recessive 48 (MRT 48) (OMIM 616269) is a recessive syndromic disorder characterized by progressive tremors, speech impairment, and behavioral problems. In the present study, we highlight a family with a case of MRT 48. The index patient was second born to healthy consanguineous parents with a history of intellectual disability. Whole exome sequencing of the patient was performed, which revealed a homozygous c.1693T>C;p.(Tyr565His) variant in the SLC6A17 gene. The variant segregated in the extended family with the phenotype. This study broadens the genotypic spectrum of SLC6A17 variants.
Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare autosomal recessive disorder that typically affects the liver, brain, and muscle. Peripheral neuropathy has not been previously associated with this condition. W...Dihydrolipoamide dehydrogenase deficiency (DLDD) is a rare autosomal recessive disorder that typically affects the liver, brain, and muscle. Peripheral neuropathy has not been previously associated with this condition. We report a novel case of DLDD in a 20-year-old woman who presented with recurrent hepatic dysfunction and progressive sensory neuropathy. Clinical evaluation, electrophysiology, and nerve biopsy revealed a severe sensory axonal neuropathy with lipid accumulation. Genetic analysis identified compound heterozygous DLD variants (c.745G>T, p.G249C; c.1344_1347del, p.D448Efs*16), and Western blotting confirmed markedly reduced DLD protein in patient-derived fibroblasts. Treatment with a branched-chain amino acid (BCAA)-free formula, methylcobalamin, and thiamine led to complete resolution of vomiting and significant improvement in neuropathic symptoms, as confirmed by follow-up nerve conduction studies. This is the first report to link DLDD with a reversible sensory neuropathy, expanding the phenotypic spectrum of the disease. Our findings suggest a role for lipid dysregulation and metabolic imbalance in the pathogenesis of peripheral nerve involvement and support early targeted dietary therapy in patients with atypical DLDD presentations.