The
gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous
missense mutations have long been associated with ...autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of
null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic
null mutations cause a severe form of neonatal dilated cardiomyopathy. Here, we expand the case series reporting two unrelated patients afflicted with early onset dilated cardiomyopathy, due to homozygosity for the p.Arg98*
variant, which had thus far been documented only in heterozygous patients and apparently healthy carriers, and the recurrent p.Arg69Alafs*8 variant, respectively. A review of previously reported biallelic
loss-of-function variants and their associated cardiac phenotypes was also performed.
An increased lifetime risk of epilepsy has been reported in neurofibromatosis type 1 (NF1) patients, ranging between 4% and 14%. To further analyze the correlation between NF1 and epilepsy, we ...retrospectively reviewed the epidemiologic, clinical, radiological, and molecular data of 784 unselected patients diagnosed with NF1 and referred to the neurofibromatosis outpatient clinics at the University Hospital of Padua. A crude prevalence of epilepsy of 4.7% was observed. In about 70% of cases, seizures arose in the context of neuroradiological findings, with the main predisposing factors being cerebral vasculopathies and hydrocephalus. In the absence of structural abnormalities, the prevalence of epilepsy was found to be 1.27%, which is approximately equal to the total prevalence in the general population. NF1 patients with seizures exhibit a higher incidence of intellectual disability and/or developmental delay, as well as of isolated learning disabilities. The comparison of causative
mutations between the two groups did not reveal a specific genotype-phenotype correlation. Our data refine the current knowledge on epileptological manifestations in NF1 patients, arguing against the hypothesis that specific mechanisms, inherent to neurofibromin cellular function, might determine an increased risk of epilepsy in this condition.
Context: Clinical hyperthyroidism is not uncommon in pregnancy, with a reported prevalence of 0.1 to 0.4%. The available antithyroid drugs are propylthiouracil and methimazole/carbimazole.
...Objectives: In this report we examined the association of both drugs with congenital malformations using data from the International Clearinghouse for Birth Defects Surveillance and Research.
Design: The study used a case-affected control analysis and included 18,131 cases with malformations and reported first-trimester exposure to medication. A total of 127 subjects were born to mothers with known first-trimester antithyroid drug exposure.
Results: Among the 52 groups of malformations that were analyzed, situs inversus ± dextrocardia, isolated unilateral kidney a/dysgenesis, and cardiac outflow tract defects were associated with prenatal exposure to propylthiouracil based on three, two, and five cases, respectively. Prenatal exposure to methimazole/carbimazole was significantly associated with choanal atresia, omphalocele, and total situs inversus ± dextrocardia (P < 0.01).
Conclusions: Further studies are required to exhaustively evaluate the associations between propylthiouracil and birth defects because of the low number, the lack of biological plausibility, and the possibility of underdiagnosis. Association between methimazole/carbimazole exposure and omphalocele and choanal atresia is consistent with previous reports and definitely suggests that these malformations could be part of a specific, even if rare, embryopathy.
Propylthiouracil is the medication of first choice in the treatment of women with hyperthyroidism in childbearing age.
Hearing loss (HL) is one of the most common sensory impairments worldwide and represents a critical medical and public health issue. Since the mid-1900s, great efforts have been aimed at ...understanding the etiology of both syndromic and non-syndromic HL and identifying correlations with specific audiological phenotypes. The extraordinary discoveries in the field of molecular genetics during the last three decades have contributed substantially to the current knowledge. Next-generation sequencing technologies have dramatically increased the diagnostic rate for genetic HL, enabling the detection of novel variants in known deafness-related genes and the discovery of new genes implicated in hearing disease. Overall, genetic factors account for at least 40% of the cases with HL, but a portion of affected patients still lack a definite molecular diagnosis. Important steps forward have been made, but many aspects still have to be clarified. In particular, the role of epigenetics in the development, function and pathology of hearing is a research field that still needs to be explored. This research is extremely challenging due to the time- and tissue-dependent variability of the epigenetic changes. Multisystem diseases are expected to be investigated at first: specific epi-signatures have been identified for several syndromic disorders and represent potential markers for molecular diagnostics.
Genetics of Coenzyme Q10 Deficiency Doimo, Mara; Desbats, Maria A.; Cerqua, Cristina ...
Molecular syndromology
5, Številka:
3-4
Journal Article
Recenzirano
Odprti dostop
Coenzyme Q10 (CoQ10) is an essential component of eukaryotic cells and is involved in crucial biochemical reactions such as the production of ATP in the mitochondrial respiratory chain, the ...biosynthesis of pyrimidines, and the modulation of apoptosis. CoQ10 requires at least 13 genes for its biosynthesis. Mutations in these genes cause primary CoQ10 deficiency, a clinically and genetically heterogeneous disorder. To date mutations in 8 genes (PDSS1, PDSS2, COQ2, COQ4, COQ6, ADCK3, ADCK4, and COQ9) have been associated with CoQ10 deficiency presenting with a wide variety of clinical manifestations. Onset can be at virtually any age, although pediatric forms are more common. Symptoms include those typical of respiratory chain disorders (encephalomyopathy, ataxia, lactic acidosis, deafness, retinitis pigmentosa, hypertrophic cardiomyopathy), but some (such as steroid-resistant nephrotic syndrome) are peculiar to this condition. The molecular bases of the clinical diversity of this condition are still unknown. It is of critical importance that physicians promptly recognize these disorders because most patients respond to oral administration of CoQ10.
Abstract
Background
Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by deafness, branchiogenic malformations and renal abnormalities. Pathogenic variants in
EYA1
,
...SIX1
and
SIX5
genes cause almost half of cases; copy number variants (CNV) and complex genomic rearrangements have been revealed in about 20% of patients, but they are not routinely and commonly included in the diagnostic work-up.
Case presentation
We report two unrelated patients with BOR syndrome clinical features, negative sequencing for BOR genes and the identification of a 2.65 Mb 8q13.2–13.3 microdeletion.
Conclusions
We highlight the value of CNV analyses in high level of suspicion for BOR syndrome but negative sequencing for BOR genes and we propose an innovative diagnostic flow-chart to increase current detection rate. Our report confirms a mechanism of non-allelic homologous recombination as causing this recurrent 8q13.2–13.3 microdeletion. Moreover, considering the role of
PRDM14
and
NCOA2
genes, both involved in regulation of fertility and deleted in our patients, we suggest the necessity of a longer follow-up to monitor fertility issues or additional clinical findings.
Cantú syndrome, or hypertrichotic osteochondrodysplasia, is a rare autosomal dominant disease characterized by congenital hypertrichosis, characteristic dysmorphisms, skeletal abnormalities and ...cardiomegaly. We report on a 7‐year‐old girl with congenital generalized hypertrichosis, coarse facial appearance and cardiac involvement, with a de novo heterozygous mutation (c.3461G > A) in the ABCC9 gene. During the annual cardiac follow‐up at the age of nine the echocardiogram showed mild left ventricular dilatation in consideration of which she started ramipril treatment. The progression of the clinical manifestations of Cantú syndrome highlights the relevance of an early diagnosis, including genetic analysis, and a multidisciplinary approach with long‐term follow‐up.
Cantú syndrome is a rare autosomal dominant disease with a marked clinical variability that can cause diagnostic and therapeutic delay. The progression of the clinical manifestations of Cantú syndrome, including the cardiac involvement, highlights the relevance of an early diagnosis with long‐term follow‐up and a multidisciplinary approach.
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