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Beta thalassaemia is one of the most common inherited haemoglobinopathies, characterised by reduced or absent production of the beta globin chain. In India, the carrier frequency of thalassaemia is estimated to be 3-4%. The prevention of Beta thalassaemia is the best strategy, and this can be achieved through carrier screening and prenatal diagnosis. Carriers of beta thalassaemia can be easily identified using haematological parameters such as complete blood count and High Performance Liquid Chromatography (HPLC) for haemoglobin analysis. The characteristic findings observed in thalassaemia carriers include microcytosis, hypochromia, with a Mean Corpuscular Volume (MCV) of less than 80 fL and Mean Corpuscular Haemoglobin (MCH) of less than 28 pg. They also present with elevated levels of HBA2 (α2δ2) ≥3.5%. Carrier screening for beta thalassaemia primarily relies on the observation of elevated HbA2 levels. However, in rare cases, some carriers can have normal HbA2 levels, leading to false-negative screening results. In a case involving a married couple who underwent routine preconceptional screening by complete blood count and HPLC for thalassaemia screening, the male partner had elevated HbA2 levels (5.2%), while the female partner had normal HbA2 levels (1.6%). Molecular testing revealed that the male partner was heterozygous for the Intervening Sequence (IVS) 1-5 (G>C) mutation, while the female partner was found to be heterozygous for the CD41-42 (-CTTT) mutation. It is important to consider molecular testing of the HBB gene in couples, even if one partner is a carrier and the other partner has normal or borderline HbA2 levels.

Beta thalassaemia is one of the most common inherited haemoglobinopathies, characterised by reduced or absent production of the beta globin chain. In India, the carrier frequency of thalassaemia is estimated to be 3-4%. The prevention of Beta thalassaemia is the best strategy, and this can be achieved through carrier screening and prenatal diagnosis. Carriers of beta thalassaemia can be easily identified using haematological parameters such as complete blood count and High Performance Liquid Chromatography (HPLC) for haemoglobin analysis. The characteristic findings observed in thalassaemia carriers include microcytosis, hypochromia, with a Mean Corpuscular Volume (MCV) of less than 80 fL and Mean Corpuscular Haemoglobin (MCH) of less than 28 pg. They also present with elevated levels of HBA2 (α2δ2) ≥3.5%. Carrier screening for beta thalassaemia primarily relies on the observation of elevated HbA2 levels. However, in rare cases, some carriers can have normal HbA2 levels, leading to false-negative screening results. In a case involving a married couple who underwent routine preconceptional screening by complete blood count and HPLC for thalassaemia screening, the male partner had elevated HbA2 levels (5.2%), while the female partner had normal HbA2 levels (1.6%). Molecular testing revealed that the male partner was heterozygous for the Intervening Sequence (IVS) 1-5 (G>C) mutation, while the female partner was found to be heterozygous for the CD41-42 (-CTTT) mutation. It is important to consider molecular testing of the HBB gene in couples, even if one partner is a carrier and the other partner has normal or borderline HbA2 levels. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Abstract Background Current world experience regarding living donor liver transplantation (LDLT) in the treatment of propionic acidemia (PA) is limited, especially in terms of using obligate heterozygous carriers as donors. This study aimed to evaluate the clinical outcomes of LDLT in children with PA. Methods From November 2017 to January 2020, 7 of the 192 children who underwent LDLT at our institution had been diagnosed with PA (median age, 2.1 years; range, 1.1–5.8 years). The primary indication for transplantation was frequent metabolic decompensations in 6 patients and preventative treatment in 1 patient. Of the seven parental living donors, six were genetically proven obligate heterozygous carriers. Results During a median follow-up of 23.9 months (range, 13.9–40.2 months), all patients were alive with 100% allograft survival, and no severe transplant-related complications occurred. In the case of liberalized protein intake, they did not suffer metabolic decompensation or disease-related complications and made progress in neurodevelopmental delay and body growth, as well as blood and urinary metabolite levels. In one patient with pre-existing mild dilated cardiomyopathy, her echocardiogram results completely normalized 13.8 months post-transplant. All living donors recovered well after surgery, with no metabolic decompensations or procedure-related complications. Western blotting revealed that the hepatic expressions of PCCA and PCCB in one of the heterozygous donors were comparable to those of the normal healthy control at the protein level. Conclusions LDLT using partial liver grafts from asymptomatic obligate heterozygous carrier donors is a viable therapeutic option for selected PA patients, with no negative impact on donors’ and recipients' clinical courses.

Gabriel Guardiola,1 Fabiola Ramos,2 Natalio Izquierdo3 1Universidad Central del Caribe School of Medicine, Bayamon, PR, US; 2Department of Ophthalmology, University of Puerto Rico School of Medicine, University of Puerto Rico, San Juan, PR, US; 3Department of Surgery, University of Puerto Rico School of Medicine, University of Puerto Rico, San Juan, PR, USCorrespondence: Natalio IzquierdoUniversity of Puerto Rico, 369 De Diego, Torre San Francisco Suite 310, San Juan, PR, 00923, USTel +1 (787) 402-0201Email njuan@msn.comPurpose: To report retinitis pigmentosa and a history of polydactyly in a Bardet–Biedl syndrome mutation carrier.Observations: A 25-year-old male presented to the clinic complaining of poor visual acuity since childhood, night-blindness, and progressive peripheral vision loss. The patient also had a history of polydactyly in both feet. Ophthalmic evaluation was remarkable for a best-corrected visual acuity of 20/400 in both eyes. Imaging revealed a “salt-and-pepper” appearance surrounding the macula, bone-spicule retinal pigment epithelium hyperplasia, paravenous retinal pigment epithelium hyperplasia, and arteriolar attenuation. In addition, bilateral macular autofluorescence with a surrounding granular hypoautofluorescence and an additional hyperautofluorescent zone was present. Full-field ERG results showed non-recordable scotopic ERG responses and diminished photopic ERG responses OU, consistent with progressive rod-cone dystrophy. Genetic testing was positive for a pathogenic heterozygous mutation in the BBS1 gene of the variant c.1169T>G (p.Met390Arg) and several variants of uncertain significance in other genes.Conclusions and Importance: Ascertainment of the inheritance patterns in BBS is an evolving discussion. Our case, a BBS carrier with retinitis pigmentosa and a history of polydactyly, could support previous research suggesting non-Mendelian genetics in this ciliopathy. Furthermore, genetic testing and analyses of additional mutations and variants of uncertain significance could potentially explain the reason for BBS-like phenotype in presumed BBS carriers.Keywords: Bardet–Biedl syndrome, heterozygous carrier, retinitis pigmentosa, polydactyly

Background: Current world experience regarding living donor liver transplantation (LDLT) in the treatment of propionic acidemia (PA) is limited, especially in terms of using obligate heterozygous carriers as donors. This study aimed to evaluate the clinical outcomes of LDLT in children with PA.Methods: From November 2017 to January 2020, 7 of the 192 children who underwent LDLT at our institution had been diagnosed with PA (median age, 2.1 years; range, 1.1-5.8 years). The primary indication for transplantation was frequent metabolic decompensations in 6 patients and preventative treatment in 1 patient. Of the seven parental living donors, six were genetically proven obligate heterozygous carriers.Results: During a median follow-up of 23.9 months (range, 13.9-40.2 months), all patients were alive with 100% allograft survival, and no severe transplant-related complications occurred. In the case of liberalized protein intake, they did not suffer metabolic decompensation or disease-related complications and made progress in neurodevelopmental delay and body growth, as well as blood and urinary metabolite levels. In one patient with pre-existing mild dilated cardiomyopathy, her echocardiogram results completely normalized 13.8 months post-transplant. All living donors recovered well after surgery, with no metabolic decompensations or procedure-related complications. Western blotting revealed that the hepatic expressions of PCCA and PCCB in one of the heterozygous donors were comparable to those of the normal healthy control at the protein level.Conclusions: LDLT using partial liver grafts from asymptomatic obligate heterozygous carrier donors is a viable therapeutic option for selected PA patients, with no negative impact on donors' and recipients' clinical courses. [ABSTRACT FROM AUTHOR]

Abstract Background Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision. Methods We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles. Results We identified five distinct mutations in four NCL‐associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL. Conclusion Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype–phenotype correlations, and prognosis.

Background: Neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision. Methods: We describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles. Results: We identified five distinct mutations in four NCL‐associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL. Conclusion: Our study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype–phenotype correlations, and prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330+2T>G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330+2T>G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study. [Copyright &y& Elsevier]

The article discusses the study on the copper (Cu) metabolism disorder Wilson's disease (WD). It states that 68 WD heterozygous carriers (WDHzc) and 31 individuals who had no family history of WD as control subjects were recruited to perform the research. It says that metabolic alterations were detected in basal ganglia in 12 WDHzc by proton magnetic resonance spectroscopy. Moreover, results show that differences in age and gender among the study groups are not statistically significant.

Bernard-Soulier syndrome (BSS) is a rare recessively inherited bleeding disorder caused by the deficiency of the platelet glycoprotein (Gp) complex Ib/IX/V that is the von Willebrand factor receptor on platelets. In patients suffering from BSS platelet adhesion is typically impaired, while platelet aggregation is normal; macrothrombocytopenia is a common feature. In this study three different families from Southern Iran were investigated. GpIb/IX/V platelet expression as detected by flow cytometry was less than 2% of normal in six cases and 12% in the remaining one. Platelet count was 35 000 platelets/microliter and iron deficiency anemia was common. All patients suffered from mucocutaneous bleeding at presentation and were born from consanguineous marriages. Genetic analysis demonstrated the presence of the same GpIX Phe55Ser missense mutation in two families and of a single base insertion (GP1BA C3221 ins), a never described mutation causing a frameshift in the GpIbα gene, in the third family. Among the family members studied several heterozygotes were identified. None of them, with one exception, had macrothrombocytopenia. In one family a slight reduction of GpIb/IX/V expression was observed. [ABSTRACT FROM AUTHOR]

Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis., Methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay., Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu., Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Fabry disease is a rare, X-chromosome-linked lysosomal storage disease caused by a deficient α-galactosidase A enzyme. The disease manifests primarily in affected hemizygous males and to some extent in heterozygous females (‘carrier’). A 45-year-old female Fabry disease patient without angiokeratomas but with numerous angiomas is presented. Her leukocyte α-galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4–1). The analysis of her α-galactosidase A gene (exon 1–7) showed the transition c.427 G>A. An intrafamilial follow-up search detected a reduced leukocyte α-galactosidase A activity in her father, who suffered exclusively from coronary heart disease. Our case report underlines the possible wide range of clinical signs in Fabry disease patients, sometimes complicated by missing typical lesions (e.g. angiokeratomas). In oligosymptomatic Fabry disease cases, genetic analysis is recommended. [ABSTRACT FROM AUTHOR]

• Heterozygous carriers of CYP21 mutations are at increased risk of developing hyperandrogenism and related comorbidities. • They frequently show hirsutism, oligomenorrhoea, overweight and a PCO-like phenotype. • 17OHP/cortisol ratio is an independent marker associated with carrier state of CAH. • Specific cut-off values of 17OHP/cortisol ratio need to be confirmed. Non-classical congenital adrenal hyperplasia (NC-CAH) includes a group of genetic disorders due to a broad class of CYP21A2 variants identifying a disease-causing 'C' genotype. The heterozygous carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism, even though clinical and laboratory characteristics are still underestimated. With the aim of obtaining a more accurate delineation of the phenotype of heterozygous carrier of CAH, we analyzed clinical, biochemical and molecular characteristics in a cohort of Sicilian subjects. Fifty-seven females with biallelic and monoallelic CYP21A2 variants classifying NC-CAH (24) and heterozygous carriers of CAH (33), respectively were selected. Forty-four females age-matched healthy controls were also enrolled and genotyped for CYP21A2. Clinical, hormonal and genetic data were collected. CYP21A2 monoallelic mutations, defining the heterozygous carriers state, were identified in subjects with clinical features including hirsutism, oligomenorrhoea, overweight and a PCO-like phenotype, particularly occurring in the age of adolescence. Consistently, levels of 17OHP and cortisol were found to be significantly different from NC-CAH. Overall, some clinical and laboratory findings including oligomenorrhea and 17OHP/cortisol ratio were observed as independent markers associated with carriers of CAH. Here we report a high prevalence of late-onset signs of polycystic ovary syndrome (PCOS) and hyperandrogenism in heterozygous carriers. The 17OHP/cortisol ratio may be a predictive tool to identify the carriers of CAH, even though specific cut-off values have not yet been identified. [ABSTRACT FROM AUTHOR]

Introduction: Various markers, such as C14:1 and the C14:1/C2 ratio, are used as diagnostic markers of very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, the levels of these markers in patients with VLCADD overlap with those in heterozygous carriers and even healthy subjects., Materials and Methods: In twenty-three affected patients and 15 heterozygous carriers with VLCADD, the accuracies of C14:1, C14:1/C12:1, C14:1/C2, and C14:1/C16 in dried blood spots (DBS) and serum were statistically estimated., Results: Among the serum markers, the sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and validity of C14:1/C12:1 were superior to those of C14:1, C14:1/C2, and C14:1/C16, but C14:1/C2 demonstrated a statistical advantage compared with only C14:1 and C14:1/C16. Elevation in serum C14:1/C12:1 was observed in only one heterozygous carrier, whereas almost half of the carriers displayed false positive results for the other markers. Among the DBS markers, although the accuracy of C14:1/C2 was ostensibly the best, no statistical significance was observed., Discussion: Serum C14:1/C12:1 might be useful for differentiating patients with VLCADD from heterozygous carriers. Although serum C14:1/C2 was significantly useful for the detection of VLCADD, this marker could not distinguish the affected patients from carriers. C14:1/C12:1 might be optimal compared with the other markers., Competing Interests: None., (© 2019 The Authors.)