ABSTRACT
Hereditary xerocytosis (HX), also known as dehydrated stomatocytosis (DHSt) is a dominantly inherited genetic disorder exhibiting red cell membrane dehydration caused by the loss of the monovalent cation K+ and water. Variants in mechanosensitive Piezo ionic channels of the PIEZO1 gene are the primary cause of HX. We have utilized high throughput and highly precise next-generation sequencing (NGS) to make a diagnosis and examine the genotype-phenotype relationship in inflexible HX cases. Seven unrelated patients with unexplained hemolytic anemia were scrutinized with a panel probing 8000 genes related to congenital anemia. Targeted next-generation sequencing identified 8 missense variants in the PIEZO1 gene in 7 unrelated Indian patients. Three of the 8 variants are novel (c.1795G > C, c.2915G > A, c.7372 T > C) and the remaining five (c.4082A > G, c.6829C > A, c.7374C > G, c.7381G > A, c.7483_7488dup) are previously reported. The variants have been validated by Sanger sequencing. One patient with autosomal dominant mutation (c.7372 T > C) is associated with iron refractory iron deficiency anemia. Of the 7 patients, one has HX in combination with a novel homozygous variant (c.994G > A) in the PKLR gene causing PK deficiency resulting in severe clinical manifestations with phenotypic variability. In silico prediction using bioinformatics tools were used to study the possible damaging effects of the novel variants. Structural-functional analysis of the novel variants was investigated by molecular modeling software (PyMOL and Swiss PDB). These results encompass the heterogeneous behavior of mechano-sensitive Piezo1 protein observed in HX patients in India. Moreover, NGS imparted a subtle, economical, and quick tool for understanding the genetic cause of undiagnosed cases of congenital hemolytic anemia. NGS grants a potential technology integrating clinical history together with molecular report profiting in such patients and their families.
Subject(s)
Anemia, Hemolytic, Congenital/genetics , Hydrops Fetalis/genetics , Ion Channels/genetics , Mutation, Missense , Adolescent , Amino Acid Sequence , Anemia, Hemolytic, Congenital/blood , Anemia, Hemolytic, Congenital/complications , Anemia, Hemolytic, Congenital/ethnology , Anemia, Iron-Deficiency/genetics , Animals , Child , Child, Preschool , Computer Simulation , Female , Genes, Dominant , Genetic Association Studies , High-Throughput Nucleotide Sequencing , Humans , Hydrops Fetalis/blood , Hydrops Fetalis/ethnology , India , Ion Channels/chemistry , Ion Channels/physiology , Iron Overload/etiology , Male , Mice , Models, Molecular , Protein Conformation , Pyruvate Kinase/genetics , Sequence Alignment , Sequence Homology, Amino Acid , Structure-Activity RelationshipABSTRACT
We report a case of fatal congenital cytomegalovirus (CMV) disease in a 695 gm, 29 weeks estimated gestational age premature infant. The newborn presented with hydrops fetalis, an unusual presentation of congenital CMV infection. In spite of ganciclovir therapy, the infant succumbed to his illness. Autopsy findings revealed the presence of widespread CMV disease, including pneumonitis, enteritis, and myocarditis. Congenital CMV infection should be considered in the differential diagnosis of hydrops fetalis.
Subject(s)
Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/complications , Hydrops Fetalis/ethnology , Infant, Premature, Diseases , Cytomegalovirus Infections/diagnosis , Fatal Outcome , Humans , Hydrops Fetalis/diagnosis , Infant, Newborn , Infant, Premature, Diseases/diagnosis , MaleABSTRACT
An unusual case of Bart's hydrops fetalis is reported where the patient was born to parents of Greek origin. An exchange transfusion was given. Adult haemoglobin (HbA) was present in addition to HbBart's and HbPortland. A low level of synthesis of alpha-chains was evident. The mother presented again in a subsequent pregnancy for prenatal diagnosis of thalassaemia. The fetus was diagnosed as an alpha-thalassaemia carrier, a diagnosis which was confirmed at birth. The nature of alpha-thalassaemia in the family is discussed.
Subject(s)
Hemoglobins, Abnormal , Hydrops Fetalis/ethnology , Thalassemia/diagnosis , Australia , Female , Greece/ethnology , Humans , Infant, Newborn , Male , Pregnancy , Prenatal DiagnosisABSTRACT
OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.