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The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
The protein-coding regions are defined as exons, and code for 21,000 genes in the human genome. This constitutes 1.5% of the genome. At least 5,000 Mendelian disorders are exonic in origin (1) The other 98.5% of the genome contains non-coding DNA, believed to be responsible for gene regulation. Non-coding regions (introns) may separate coding genes or be interspersed among exons of a clinically significant gene. At a single genetic locus, many different nuclear mutations may arise. In compound heterozygosity, two different alleles may show different base mutations, each deleterious. Causative mutant alleles influencing a single phenotype may exist in two different genetic loci (mixed heterozygosity). It follows that both genes are necessary for a normal phenotype.
The Porphyrias
Published in Henry W. Lim, Nicholas A. Soter, Clinical Photomedicine, 2018
Molecular analysis of the ALA dehydratase defect was carried out in two patients. The first study was made in a German patient with an onset of symptoms in his teens (49,50). This patient was found to have two separate point mutations, one in each ALA dehydratase allele (50,51), which were compatible with compound heterozygosity. One point mutation was a substitution of A for G at nucleotide 820, which resulted in amino acid substitution from alanine to threonine at position 274. The other was a C to T transition resulting in an arginine to tryptophan substitution at position 240. The functional studies of these mutations demonstrated that the former yields an unstable enzyme, while the latter encodes a catalytically inactive enzyme (51). Compound heterozygosity was subsequently also demonstrated in another patient who developed the disease early in childhood (52). Since all heterozygotes of ALA dehydratase deficiency had no clinical consequences, these defects may be widely found as germ-line mutations. Heterozygous subjects for ALA dehydratase deficiency, however, may be at a high risk for the toxic effects of chemicals or metals known to affect ALA dehydratase activity adversely (53).
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: autosomal recessive; many affected individuals present nonsense mutations in exon 1 of MESP2, which are predicted to result in nonsense-mediated decay. In some cases compound heterozygosity for a nonsense mutation and a missense mutation has been found. STD is frequent in Spanish Puerto Ricans, presumably as a result of the MESP2 founder mutation, p.Glu103X (E103X). Studies in the mouse demonstrate that Mesp2 is expressed in the anterior somitic compartment and is essential in the somite-boundary formation, a crucial step for the formation of vertebrae, which occur through a process called resegmentation, in which the caudal half of one somite fuses to the rostral half of the next somite in a rostrocaudal order. MESP2 mutations also cause SCD2.
Multimodal imaging in Schubert-Bornschein congenital stationary night blindness
Published in Ophthalmic Genetics, 2023
Maurizio Battaglia Parodi, Alessandro Arrigo, Firuzeh Rajabian, Ahmad Mansour, Stefano Mercuri, Vincenzo Starace, Alessandro Bordato, Maria Pia Manitto, Elisabetta Martina, Francesco Bandello
We included three patients suffering of CSNB Schubert-Bornschein subtype, two with cCSNB and one with iCSNB. Genetic analyses revealed that two patients had pathogenic variant on TRPM1 gene, on chromosome 15q: one with the homozygous pathogenic variant c.545-3C>G, p.(?); the other with the pathogenic variants c.1314 G>A, p.(=) and c.54 + 5 G>A, p.(?) (compound heterozygosity). The last patient had the c.3011T>G, p.(Met1004Arg) pathogenic variant on gene CACNA1F, chromosome X. Complete patients’ data are listed in Table 1. All patients were male, with a mean age of 28 + 9.53 SD. Medical history was negative, except for the night blindness since early childhood. Patients had a mean BCVA of 0.24 ± 0.04 LogMAR, whereas healthy subjects had a BCVA of 0.0 ± 0.0 SD LogMAR.
Missing Hb Q-India Peak in a Triple-Heterozygous Patient with Hb D-Punjab/Hb Q-India/β-Thalassemia Trait
Published in Hemoglobin, 2020
Praveen Sharma, Aditya Jandial, Sangamitra Rajasekaran, Reena Das, Sanjeev Chhabra, Jasbir Kaur Hira, Alka Rani Khadwal, Pankaj Malhotra, Prashant Sharma
Cation exchange high performance liquid chromatography (HPLC) (VARIANT II™, β-Thalassemia Short Program; Bio-Rad Laboratories, Hercules, CA, USA) done 3 months post-transfusion revealed reduced adult Hb (Hb A, 3.2%), 1.1% Hb F and variant peaks in the D- and C-windows (78.9 and 13.3%, respectively) [Figure 1(A)]. Hb A2 (2.3%) was falsely reduced due to interference by the D-peak. Cellulose acetate electrophoresis (CAE), at pH 8.6 showed slow-moving bands in D/S/G and C/E/O/A2 regions [Figure 1(B), lane 3]. Densitometry of the electrophoretic gel revealed the C/E/O/A2 region band to comprise 19.3%. This pattern did not fit with any known patterns of compound heterozygosity, and thus, family studies and genetic testing were advised.
Co-inheritance of HBB:c.−106G > C, a rare single nucleotide variation at position −56 relative to transcription initiation site, with other known mutations in the globin clusters
Published in Hematology, 2018
Margherita Vinciguerra, Cristina Passarello, Filippo Cassarà, Filippo Leto, Monica Cannata, Elisa Ferro, Davide Anzà, Giuseppina Calvaruso, Aurelio Maggio, Antonino Giambona
Eight patients in heterozygous state showed normal haematological and electrophoretic values so it is impossible to distinguish it from a non-carrier subject. The phenotype of patient with compound heterozygosity for HBB: c.−106G > C and Hb S was not associated with phenotypic variations respect to the phenotype of the simple βS-allele carrier. The co-inheritance of HBB: c.−106G > C, the beta-thalassaemic allele IVS-I-1 G->A [NM_000518.4 (HBB):c.92 + 1G > A] and ααα anti3.7 rearrangement, observed in one patient, showed the same phenotype of the compound heterozygosity for β0-thalassaemia and ααα anti3.7 rearrangement.