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Background: The MSH3 gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3 germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients' tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3 deficiency., Methods: We report five new unrelated patients with MSH3 -associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far., Results: All patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3 deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3 deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion., Conclusion: This report lends further credence to biallelic MSH3 germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3 to dedicated diagnostic gene panels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra-colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the "colorectal cancer or polyposis" series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra-digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra-colonic surveillance has to be defined., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Congenital hemolytic anemia constitutes a heterogeneous group of rare genetic disorders of red blood cells. Diagnosis is based on clinical data, family history and phenotypic testing, genetic analyses being usually performed as a late step. In this study, we explored 40 patients with congenital hemolytic anemia by whole exome sequencing: 20 patients with hereditary spherocytosis and 20 patients with unexplained hemolysis., Results: A probable genetic cause of disease was identified in 82.5% of the patients (33/40): 100% of those with suspected hereditary spherocytosis (20/20) and 65% of those with unexplained hemolysis (13/20). We found that several patients carried genetic variations in more than one gene (3/20 in the hereditary spherocytosis group, 6/13 fully elucidated patients in the unexplained hemolysis group), giving a more accurate picture of the genetic complexity of congenital hemolytic anemia. In addition, whole exome sequencing allowed us to identify genetic variants in non-congenital hemolytic anemia genes that explained part of the phenotype in 3 patients., Conclusion: The rapid development of next generation sequencing has rendered the genetic study of these diseases much easier and cheaper. Whole exome sequencing in congenital hemolytic anemia could provide a more precise and quicker diagnosis, improve patients' healthcare and probably has to be democratized notably for complex cases.

A pyrimidine 5'-nucleotidase deficiency in an adult is reported. Interestingly, the P5'N-1 deficiency was associated to a polymalformative syndrome and was characterized by a chronic, pancytopenic evolution with concomitant dyserythropoiesis.

Aldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease.

Introduction: Muscle phosphofructokinase deficiency, the seventh member of the glycogen storage diseases family, is also called Tarui's disease (GSD VII)., Methods: We studied two patients in two unrelated families with Tarui's disease, analyzing clinical features, CK level, EMG, muscle biopsy findings and molecular genetics features. Metabolic muscle explorations (forearm ischemic exercise test [FIET]; bicycle ergometer exercise test [EE]; 31P-nuclear magnetic resonance spectroscopy of calf muscle [31P-NMR-S]) are performed as appropriate., Results: Two patients, a 47-year-old man and a 38-year-old woman, complained of exercise-induced fatigue since childhood. The neurological examination was normal or showed light weakness. Laboratory studies showed increased CPK, serum uric acid and reticulocyte count without anemia. There was no increase in the blood lactate level during the FIET or the EE although there was a light increase in the respiratory exchange ratio during the EE. 31P-NMR-S revealed no intracellular acidification or accumulated intermediates such as phosphorylated monoesters (PME) known to be pathognomic for GSD VII. Two new mutations were identified., Discussion: FIET and EE were non-contributive to diagnosis, but 31P-NMR provided a characteristic spectra of Tarui's disease, in agreement with phosphofructokinase activity level in erythrocytes. Muscle biopsy does not always provide useful information for diagnosis. In these two cases, genetic studies failed to establish a genotype-phenotype correlation., Conclusion: The search for phosphofructokinase deficiency should be continued throughout life in adults experiencing fatigability or weakness because of the severe disability for daily life activities caused by the late onset form., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

We present a rapid strategy based on Restriction Fragment Length Polymorphism (RFLP) analysis to characterize the more frequent glucose 6-phosphate dehydrogenase (G6PD) variants observed in a population with high gene flow. During a study involving more than 600 patients, we observed mainly G6PD A(-) (c.202G>A, c.376A>G; p.Val68Met, p.Asn126Asp), G6PD Mediterranean (Med) (c.563C>T, p.Ser188Phe), and G6PD Betica (c.376A>G, 542A>T; p.126Asn>Asp, 181Asp>Val) with addition of a few rare ones. A number of 10 abnormalities amounted to 92% of all the molecular defects. In addition, seven new mutations were found: three presented with acute hemolytic anemia following oxidative stress [G6PD Nice (c.1380G>C, p.Glu460Asp), G6PD Roubaix (c.811G>C, p.Val271Leu), and G6PD Toledo (c.496C>T, p.Arg166Cys)], three with different degrees of chronic hemolytic anemia [G6PD Lille (c.821A>T, p.Glu274Val), G6PD Villeurbanne (c.1000_1002delACC, p.Thr334del), and G6PD Amiens (c.1367A>T, p.Asp456Val)] and one found fortuitously G6PD Montpellier (c.1132G>A, p.Gly378Ser).

We report the second documented observation of a rare class-III variant, we named G6PD Pyrgos, [c.383 T>G, p.128Leu>Arg] found in a Greek family. A 3-dimensional structure model for the enzyme shows that the region modified by the substitution is identical to that modified in G6PD A(-) (68Val>Met, 126Asn>Asp), suggesting a common underlying pathophysiological mechanism. Observation of this mutation in different Mediterranean regions suggests that it might be more widespread that initially supposed and, in the absence of molecular characterization, could be confused with other frequent variants.

Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A1*2C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A1*2C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators., (Copyright 2008 Wiley-Liss, Inc.)

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance., ((c) 2007 Wiley-Liss, Inc.)

The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene (MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR([230-314 microg/day]) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR([230-314 microg/day]) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts., ((c) 2007 Wiley-Liss, Inc.)

The SFTPB gene indel g.1549C > GAA (121ins2) accounts for about 2/3 of the mutant alleles underlying complete surfactant protein B deficiency. It is unclear, however, whether its prevalence is due to recurrent mutation or a founder effect. The underlying mutational mechanism was therefore sought through the analysis of local DNA sequence complexity. A relatively complex two-step process was proposed: the first step involving slipped mispairing mediated by a direct repeat and generating an AGAA micro-insertion, the second step involving hairpin loop resolution resulting in a CA micro-deletion. The possibility of a founder effect was then assessed by typing 8 intragenic SNPs in 17 independent 121ins2 chromosomes from 10 probands, with parental non-121ins2 chromosomes serving as controls. The 121ins2 chromosomes were assigned to three discrete haplotypes, whilst control chromosomes were distributed between 10 of the 11 observed parental haplotypes. The 121ins2 mutation was in strong and significant linkage disequilibrium (LD) with the tightly linked marker g.1580T/C (|D'| = 1; P approximately 0.024), although only moderate LD was found with the rest of the locus (|D'| approximately 0.54; P approximately 0.136). Data on haplotype structure and the locus LD pattern, obtained from 81 independent Western-European chromosomes, were consistent with the three mutation-bearing haplotypes having originated from a common ancestor by recombination. Interestingly, all families harboring the 121ins2 indel had ancestors from a region of Northwestern Europe populated by Frankish/Saxon migration. Taken together, these data are consistent with the view that an indel mutation occurred on a relatively common SFTPB haplotype and now accounts for the majority of (and possibly all) extant 121ins2 chromosomes., ((c) 2005 Wiley-Liss, Inc.)

Background: Orofacial clefts are among the most frequent congenital malformations at birth with a prevalence of 1 in 700 births in Europe. The implication of environmental factors in their etiology has been demonstrated. The role of folic acid, or folates, in the prevention of orofacial clefts is still debated although its efficacy has been demonstrated for the prevention of neural tube defects., Methods: A case-control study was conducted in 7 hospitals in 4 centers in France. Cases (N=240) were children with non-syndromic orofacial cleft referred to one of the study hospitals for initial surgical repair in 1998 and 1999. Controls (N=236) matched for gender, geographic origin, and age were chosen in paediatric departments of the same hospitals. Usual dietary intake of folates was estimated using a food frequency questionnaire submitted to the mother at hospital. During the same interview, data on sociodemographic characteristics, medical and obstetrical history, tobacco and alcohol consumption, and vitamin supplements, were obtained. Odds ratios associated with quintiles of dietary intake of folates were estimated using logistic regression adjusting for known confounders., Results: A significant dose-response relationship between the risk of orofacial clefts and a decrease in the intake of folates from diet was found, stronger for cleft palate without cleft lip. Only few women (<1%) declared having taken vitamin supplements containing folic acid when planning their pregnancy., Conclusion: Our study further suggests that folates are useful for the prevention of orofacial clefts during the periconceptual period. In our study, the estimated average daily intake of folates (270 microg/day) was below French national recommendations for the prevention of neural tube defects (400 microg/day). Since those insufficient folate intakes during the periconceptual period are not presently met by vitamin supplementation, the solution may come from the food fortification program proposed and implemented by the National Agency for Food Safety (AFSSA).

Background: Abnormalities of the intracellular metabolism of the hydrophobic surfactant proteins SP-B and SP-C and their precursors may be causally linked to chronic childhood diffuse lung diseases. The profile of these proteins in the alveolar space is unknown in such subjects., Methods: We analyzed bronchoalveolar lavage fluid by Western blotting for SP-B, SP-C and their proforms in children with pulmonary alveolar proteinosis (PAP, n = 15), children with no SP-B (n = 6), children with chronic respiratory distress of unknown cause (cRD, n = 7), in comparison to children without lung disease (n = 15) or chronic obstructive bronchitis (n = 19)., Results: Pro-SP-B of 25-26 kD was commonly abundant in all groups of subjects, suggesting that their presence is not of diagnostic value for processing defects. In contrast, pro-SP-B peptides cleaved off during intracellular processing of SP-B and smaller than 19-21 kD, were exclusively found in PAP and cRD. In 4 of 6 children with no SP-B, mutations of SFTPB or SPTPC genes were found. Pro-SP-C forms were identified at very low frequency. Their presence was clearly, but not exclusively associated with mutations of the SFTPB and SPTPC genes, impeding their usage as candidates for diagnostic screening., Conclusion: Immuno-analysis of the hydrophobic surfactant proteins and their precursor forms in bronchoalveolar lavage is minimally invasive and can give valuable clues for the involvement of processing abnormalities in pediatric pulmonary disorders.

Background: Maternal alcohol consumption has been associated with an increased risk of nonsyndromic oral clefts in some studies. Study of gene-environment interaction may provide insight into the reasons for their discrepancies observed. We focused on a polymorphism of the ADH1C gene (third gene of the class I alcohol dehydrogenase family), involved in the metabolism of ethanol and other alcohols., Methods: Data come from a French case-control study (1998-2001), which tested the association between maternal alcohol consumption during the first trimester of pregnancy and the risk of nonsyndromic oral clefts (240 cases, 236 controls). A case-parent study design looked at the association with an ADH1C polymorphism (Ile349Val site) and potential gene-environment interaction effects. A log-linear model was used to distinguish the direct effect of the child's genotype from the maternally mediated effects., Results: An increased risk of nonsyndromic oral clefts was observed for women who reported drinking alcohol during the first trimester, compared with women who did not. The mutated ADH1C allele carried by the child seemed to have a protective effect against the risk of oral clefts (RRone copy, 0.71; 95% confidence interval [CI], 0.50-1.02; RRtwo copies, 0.63; 95% CI, 0.3-1.3). The maternal genotype played a less important role than the child's, and its action remains unclear. No significant evidence of interaction effects between the ADH1C genotype and maternal alcohol consumption was observed., Conclusions: Because the ADH1C gene is involved in the metabolic pathways of many alcohols, we propose several hypotheses about the causal pathway, including ethanol oxidation activity and, more probably, retinol oxidation.

Pulmonary surfactant protein C (SP-C) is a highly hydrophobic peptide produced by type-II alveolar cells through the processing of a high-molecular weight precursor (pro-SP-C), that enhances surface tension and facilitates the recycling of pulmonary surfactant in vitro. Recently, two seemingly dominant-negative mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in families with vertically-inherited interstitial lung disease (Nogee et al. [2001: N Engl J Med 344:573-579]; Thomas et al. [2002: Am J Respir Crit Care Med 165:1322-1328]). We have examined the SP-C protein and its precursor as well as the encoding gene, in a cohort of 34 sporadic or familial cases with unexplained respiratory distress (URD) in which surfactant protein B (SP-B) deficiency related to SFTPB mutation had been ruled out. One patient with complete SP-C deficiency had no detectable mutation of SFTPC. Of the 10 patients with abnormal pro-SP-C processing, as suggested from analysis of broncho-alveolar lavage (BAL) fluid, two distinct heterozygous SFTPC missense mutations were identified. The first, g.1286T > C (p.I73T), was de novo and resulted in progressive respiratory failure with intra-alveolar storage of a granular, protein- and lipid-rich, periodic acid Schiff (PAS)-positive material (pulmonary alveolar proteinosis (PAP)), and interstitial lung disease. The second, g.2125G > A (p.R167Q), was found in two PAP patients from the endogamous white settler population of Réunion Island in which URD has an unexpectedly high prevalence. Since this mutation was diagnosed in subjects from this subpopulation who did not have evidence for lung disease, we propose environmental exposures or modifier genes to play a role in the phenotype, as suggested from murine models lacking the SP-C protein, although we cannot rule out a rare polymorphism, hitherto restricted to that subpopulation. Most remarkably, these observations extend the phenotypic spectrum related to SFTPC mutation from interstitial lung disease to PAP. Notably, the reported mutations do not appear to be dominant negatives. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html., (Copyright 2004 Wiley-Liss, Inc.)