Delineation of the adult phenotype of Coffin-Siris syndrome in 35 individuals.

Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.

Validation of clinical exome sequencing in the diagnostic procedure of patients with intellectual disability in clinical practice.

Intellectual disability (ID) has a prevalence of 1-3% and aproximately 30-50% of ID cases have a genetic cause. Development of next-generation sequencing has shown a high diagnostic potential. The aim of this work was to evaluate the diagnostic yield of clinical exome sequencing in 188 ID patients and the economic impact of its introduction in clinical practice. An analysis of diagnostic yield according to the different clinical variables was performed in order to establish an efficient diagnostic protocol for ID patients. Diagnostic yield of clinical exome sequencing was significant (34%) supporting its utility in diagnosis of ID patients. Wide genetic heterogeneity and predominance of autosomal dominant de novo variants in ID patients were observed. Time to diagnosis was shortened and diagnostic study costs decreased by 62% after implementation of clinical exome sequencing. No association was found between any of the variables analyzed and a higher diagnostic yield; added to the fact that many of the diagnoses weren't clinically detectable, the reduction of time to diagnosis and the economic savings with respect to classical diagnostic studies, strengthen the clinical and economical convenience of early implementation of clinical exome sequencing in the diagnostic workup of ID patients in clinical practice.

Expresividad extremadamente variable en el síndrome de Smith-Lemli-Opitz: revisión de 4 casos clínicos / Extremely variable expressivity in Smith-Lemli-Opitz syndrome: Review of 4 cases

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PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals.

In 2016 and 2018, Chung, Jansen and others described a new syndrome caused by haploinsufficiency of PHIP (pleckstrin homology domain interacting protein, OMIM *612,870) and mainly characterized by developmental delay (DD), learning difficulties/intellectual disability (ID), behavioral abnormalities, facial dysmorphism and obesity (CHUJANS, OMIM #617991). So far, PHIP alterations appear to be a rare cause of DD/ID. "Omics" technologies such as exome sequencing or array analyses have led to the identification of distinct types of alterations of PHIP, including, truncating variants, missense substitutions, splice variants and large deletions encompassing portions of the gene or the entire gene as well as adjacent genomic regions. We collected clinical and genetic data of 23 individuals with PHIP-associated Chung-Jansen syndrome (CHUJANS) from all over Europe. Follow-up investigations (e.g. Sanger sequencing, qPCR or Fluorescence-in-situ-Hybridization) and segregation analysis showed either de novo occurrence or inheritance from an also (mildly) affected parent. In accordance with previously described patients, almost all individuals reported here show developmental delay (22/23), learning disability or ID (22/23), behavioral abnormalities (20/23), weight problems (13/23) and characteristic craniofacial features (i.e. large ears/earlobes, prominent eyebrows, anteverted nares and long philtrum (23/23)). To further investigate the facial gestalt of individuals with CHUJANS, we performed facial analysis using the GestaltMatcher approach. By this, we could establish that PHIP patients are indistinguishable based on the type of PHIP alteration (e.g. missense, loss-of-function, splice site) but show a significant difference to the average face of healthy individuals as well as to individuals with Prader-Willi syndrome (PWS, OMIM #176270) or with a CUL4B-alteration (Intellectual developmental disorder, X-linked, syndromic, Cabezas type, OMIM #300354). Our findings expand the mutational and clinical spectrum of CHUJANS. We discuss the molecular and clinical features in comparison to the published individuals. The fact that some variants were inherited from a mildly affected parent further illustrates the variability of the associated phenotype and outlines the importance of a thorough clinical evaluation combined with genetic analyses for accurate diagnosis and counselling.

Risk of mayor and minor birth defects in children conceived by assisted reproductive technology (IVF/ICSI): A prospective controlled cohort study.

INTRODUCTION: About 0.2-6.1% of newborns in the developed world have been conceived by assisted reproductive techniques (ART). Higher rate of major and minor malformations have been described in this population, but the multiple possible confounders associated make it difficult to establish a direct causal relationship and the specific factors involved. MATERIAL AND METHODS: To determine the risk of these malformations in our population, a collaborative prospective controlled cohort study was designed. We collected the specific ART-data related to the clinical gestation of women treated in a period of 2 years in the Reproduction Unit from a Spanish public tertiary-level hospital. 231 out of 267 newborns of these gestation (88%) participated in the study and were assessed by a pediatrician with expertise in Clinical Genetics and Dysmorphology at 12-20 and 26-40 months of age. At the same time a controlled group of children naturally conceived (NC) was selected according to the following criteria: the next NC newborn belonging to the same group of maternal and gestational age, and type of gestation (single or multiple). 230 controls were chosen and 208 participated in the study (90%). RESULTS: Major malformations were presented in 7.8% of the ART-children and 7.2% of the controls, without founding statistically differences between groups. However, differences were found in the risk of some minor malformations such as capillary malformations and pigmentary lesions, higher in the ART-group. A recurrent pattern of craneofacial anomalies was also unexpectedly detected. CONCLUSIONS: In spite of the high rate of major congenital malformations detected, there were no differences between groups. Thus, our results suggest that ART may affect the normal embryonic development but in a milder way than other confounding factors do. The facial phenotype identified has not previously been described, either the higher risk of capillary malformations and pigmentary lesions. More studies are needed to confirm this association.

Riesgo de malformaciones mayores y menores en niños concebidos por técnicas de reproducción asistida (FIV/ICSI): estudio prospectivo de cohorte controlado / Risk of mayor and minor birth defects in children conceived by assisted reproductive technology (IVF/ICSI): A prospective controlled cohort study

Introducción: En torno al 0,2-6,1% de los recién nacidos en los países desarrollados han sido concebidos por técnicas de reproducción asistida (TRA). Se han descrito tasas más altas de malformaciones congénitas (MC) mayores y menores en esta población, pero los múltiples posibles factores de confusión asociados hacen difícil establecer una relación de causalidad directa con estos procedimientos y conocer los factores específicos implicados. Material y método: Se realizó un estudio prospectivo de cohorte controlado con el objetivo de determinar el riesgo de MC en niños-TRA. Se recogieron los datos específicos de la TRA de una cohorte de gestaciones clínicas de mujeres tratadas en la Unidad de Reproducción de un hospital público de tercer nivel durante dos años; 231 de 267 (87%) niños nacidos de dichas gestaciones-TRA participaron en el estudio y fueron valorados por un pediatra con formación en Genética Clínica y Dismorfología a los 12-20 y a los 26-40 meses de edad. De forma simultánea se seleccionó una cohorte de niños concebidos de forma natural (CN), de acuerdo con los criterios: siguiente recién nacido al caso del mismo grupo de edad materna, edad gestacional y tipo de gestación (única o múltiple); 230 niños CN fueron seleccionados y 208 (90%) participaron en el estudio. Resultados: Se detectaron MC mayores en el 7,8% de casos y en el 7,2% de controles, sin existir diferencias estadísticamente significativas entre ellos. Sí se identificaron diferencias en algunas malformaciones menores como las malformaciones capilares y lesiones pigmentarias, más frecuentes en el grupo TRA. Además, se identificó de forma inesperada un patrón craneofacial recurrente en el grupo TRA. (AU)

Introduction: About 0.2–6.1% of newborns in the developed world have been conceived by assisted reproductive techniques (ART). Higher rate of major and minor malformations have been described in this population, but the multiple possible confounders associated, make it difficult to establish a direct causal relationship, and the specific factors involved. Material and methods: To determine the risk of these malformations in our population, a collaborative prospective controlled cohort study was designed. We collected the specific ART-data related to the clinical gestation of women treated in a period of 2 years in the Reproduction Unit from a Spanish public tertiary-level hospital. 231 out of 267 newborns of these gestation (88%) were exhausted assessed by a Clinical Geneticist expertise in Dysmorphology at 12–20 and 26–40 months of age. At the same time a controlled group of children naturally conceived (NC) was selected according to the following criteria: the next NC newborn belonging to the same group of maternal and gestational age, and type of gestation (single or multiple). 230 controls were chosen and 208 participated in the study (90%). Results: Major malformations were presented in 7.8% of the ART-children and 7.2% of the controls, without founding statistically differences between groups. However, differences were found in the risk of some minor malformations such as capillary malformations and pigmentary lesions, higher in the ART-group. A recurrent pattern of craneofacial anomalies was also unexpectedly detected. (AU)

[Risk of mayor and minor birth defects in children conceived by assisted reproductive technology (IVF/ICSI): A prospective controlled cohort study]. / Riesgo de malformaciones mayores y menores en niños concebidos por técnicas de reproducción asistida (FIV/ICSI): estudio prospectivo de cohorte controlado.

INTRODUCTION: About 0.2-6.1% of newborns in the developed world have been conceived by assisted reproductive techniques (ART). Higher rate of major and minor malformations have been described in this population, but the multiple possible confounders associated, make it difficult to establish a direct causal relationship, and the specific factors involved. MATERIAL AND METHODS: To determine the risk of these malformations in our population, a collaborative prospective controlled cohort study was designed. We collected the specific ART-data related to the clinical gestation of women treated in a period of 2 years in the Reproduction Unit from a Spanish public tertiary-level hospital. 231 out of 267 newborns of these gestation (88%) were exhausted assessed by a Clinical Geneticist expertise in Dysmorphology at 12-20 and 26-40 months of age. At the same time a controlled group of children naturally conceived (NC) was selected according to the following criteria: the next NC newborn belonging to the same group of maternal and gestational age, and type of gestation (single or multiple). 230 controls were chosen and 208 participated in the study (90%). RESULTS: Major malformations were presented in 7.8% of the ART-children and 7.2% of the controls, without founding statistically differences between groups. However, differences were found in the risk of some minor malformations such as capillary malformations and pigmentary lesions, higher in the ART-group. A recurrent pattern of craneofacial anomalies was also unexpectedly detected. CONCLUSIONS: In spite of the high rate of major congenital malformations detected, there were no differences between groups. Thus, our results suggest that ART may affect the normal embryonic development but in a milder way than other confounding factors do. The facial phenotype identified has not previously, either the higher risk of capillary malformations and pigmentary lesions. More studies are needed to confirm this association.

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.

Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.

More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported. Subsequently, we review the clinical and radiological findings of the 14 reported ODCD patients. The majority of ODCD patients are compound heterozygotes for TRIP11 variants, 12/14 have a null allele and a splice variant whilst one is homozygous for an in-frame splicing variant, with the splice variants resulting in residual GMAP activity and hypothesized to explain why they have ODCD and not ACG1A. However, adult patient 4 has two potentially null alleles and it remains unknown why she has very mild clinical features. The c.586C>T; p.(Gln196*) variant, previously shown by mRNA studies to result in p.Val105_Gln196del, is the most frequent variant, present in seven individuals from four families, three from different regions of the world, suggesting that it may be a variant hotspot. Another variant, c.2993_2994del; p.(Lys998Serfs*5), has been observed in two individuals with a possible common ancestor. In summary, although there are clinical and radiological characteristics common to all individuals, we demonstrate that the clinical spectrum of TRIP11-associated dysplasias is even more diverse than previously described and that common genetic variants may exist.

Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients.

BACKGROUND: Acute intermittent porphyria (AIP) is a genetic disease characterized by acute neurovisceral attacks. Long-term clinical conditions, chronic symptoms and impaired health related quality of life (HRQoL) have been reported during non-attack periods but mainly in patients with recurrent attacks. Our aim was to investigate these aspects in sporadic AIP (SA-AIP) and latent AIP (L-AIP) patients. Fifty-five participants, 27 SA-AIP (< 4 attacks/year) and 28 L-AIP patients with a prevalent founder mutation from Spain were included. Medical records were reviewed, and individual interviews, physical examinations, biochemical analyses, and abdominal ultrasound scans were conducted. HRQoL was assessed through an EQ-5D-5L questionnaire. A comparative study was made between SA-AIP and L-AIP patients. RESULTS: The earliest long-term clinical condition associated with SA-AIP was chronic kidney disease. Chronic symptoms were reported in 85.2 % of SA-AIP and 46.4 % of L-AIP patients. Unspecific abdominal pain, fatigue, muscle pain and insomnia were significantly more frequent in SA-AIP than in L-AIP patients. The EQ-5D-5L index was lower in SA-AIP (0.809 vs. 0.926, p = 0.0497), and the impact of "pain", "anxiety-depression" and "mobility" was more intense in the EQ-5D-5L domains in SA-AIP than in L-AIP subjects and the general Spanish population. CONCLUSIONS: AIP remains a chronically symptomatic disease that adversely affects health and quality of life, even in patients with low rate of acute attacks. We suggest a regular monitoring of patients with symptomatic AIP regardless of their attack rate or the time since their last attack, with proper pain management and careful attention to kidney function.

Evaluación del desarrollo psicomotor hasta los 3 años de edad de niños españoles concebidos por técnicas de reproducción asistida (FIV/ICSI): estudio prospectivo de cohorte controlado / Assessment of psychomotor development of Spanish children up to 3 years of age conceived by assisted reproductive techniques: Prospective matched cohort study

INTRODUCCIÓN: Más de 5 millones de niños han sido concebidos por técnicas de reproducción asistida (TRA) a nivel mundial. Aunque la mayoría de los autores no detecta diferencias en cuanto a desarrollo psicomotor, los resultados son aún contradictorios. OBJETIVO: Conocer si los niños-TRA tienen más riesgo de trastorno del neurodesarrollo y describir posibles factores de la TRA asociados. MATERIAL Y MÉTODOS: Evaluación de niños concebidos por TRA hasta los 3 años de edad, nacidos de una cohorte de mujeres tratadas en la unidad de reproducción asistida de un hospital terciario desde mayo de 2012 hasta mayo de 2014; evaluación de controles pareados: siguiente recién nacido al caso concebido de forma natural, del mismo grupo de edad materna, gestacional y mismo tipo de gestación. RESULTADOS: Hubo 243 gestaciones clínicas y nacieron 267 niños-TRA. Fueron evaluados 231 (87%). Simultáneamente se evaluaron 208/230 controles (90%). No hubo diferencias estadísticamente significativas en trastornos del neurodesarrollo (retraso global del desarrollo, trastorno del espectro autista o retraso del leguaje). El análisis estadístico multivariante de posibles factores de la TRA asociados solo mostró asociación entre transferencia de embrión congelado y retraso del lenguaje. CONCLUSIONES: No se han detectado diferencias en trastornos del neurodesarrollo tras ajustar los resultados por edad materna, gemelaridad y otros posibles factores de confusión, lo que apoya que estos factores deben jugar un papel más importante que las propias TRA. La asociación entre transferencia de embrión congelado y retraso del lenguaje no ha sido descrita previamente. Son necesarios estudios a largo plazo en niños concebidos tras transferencia de embrión congelado para corroborar estos resultados

INTRODUCTION: More than five million children have been conceived by assisted reproductive techniques (ART) around the world. Most authors agree that there are no differences in psychomotor development in comparison to naturally conceived children. However, these results are still contradictory. OBJECTIVE: To determine whether children born from a cohort of ART-clinical gestations have a higher risk of suffering neurodevelopmental disorders in comparison to a control group. The potential associated ART-factors associated were also determined. MATERIAL AND METHODS: The study included the assessment of children up to 3 years old conceived by ART, and born from a cohort of women treated by the reproduction unit of a public hospital from May 2012 to May 2014. A simultaneous assessment was made of matched controls, by following the newborn naturally conceived after the ART-case, of the same group of maternal age, gestational age, and type of gestation. RESULTS: There were 243 clinical gestations and 267 ART-newborns, of which 231 were assessed (87%). A simultaneous assessment was carried out in 208/230 controls (90%). There were no differences in neurodevelopmental disorders (global developmental delay, autism spectrum or language delay). Multivariate analysis of potential ART factors only showed an association between transfer of frozen embryos with language delay that has not been previously described. CONCLUSIONS: There were no differences between groups after adjusting the results according to maternal age, multiple pregnancy, and other possible confounding factors, supporting that the role of these factors may be more relevant than the ART itself. The association between frozen embryo transfer and language delay has not been previously described. Thus, more studies are needed to confirm or refute this relationship

Primer caso español de discapacidad intelectual sindrómica con dismorfia facial, crisis y anomalías de extremidades por mutaciones bialélicas en el gen OTUD6B / First Spanish case of syndromic intellectual disability with dysmorphic facies, seizures, and distal limb anomalies caused by balletic mutations in the OTUD6B gene

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[Assessment of psychomotor development of Spanish children up to 3 years of age conceived by assisted reproductive techniques: Prospective matched cohort study]. / Evaluación del desarrollo psicomotor hasta los 3 años de edad de niños españoles concebidos por técnicas de reproducción asistida (FIV/ICSI): estudio prospectivo de cohorte controlado.

INTRODUCTION: More than five million children have been conceived by assisted reproductive techniques (ART) around the world. Most authors agree that there are no differences in psychomotor development in comparison to naturally conceived children. However, these results are still contradictory. OBJECTIVE: To determine whether children born from a cohort of ART-clinical gestations have a higher risk of suffering neurodevelopmental disorders in comparison to a control group. The potential associated ART-factors associated were also determined. MATERIAL AND METHODS: The study included the assessment of children up to 3 years old conceived by ART, and born from a cohort of women treated by the reproduction unit of a public hospital from May 2012 to May 2014. A simultaneous assessment was made of matched controls, by following the newborn naturally conceived after the ART-case, of the same group of maternal age, gestational age, and type of gestation. RESULTS: There were 243 clinical gestations and 267 ART-newborns, of which 231 were assessed (87%). A simultaneous assessment was carried out in 208/230 controls (90%). There were no differences in neurodevelopmental disorders (global developmental delay, autism spectrum or language delay). Multivariate analysis of potential ART factors only showed an association between transfer of frozen embryos with language delay that has not been previously described. CONCLUSIONS: There were no differences between groups after adjusting the results according to maternal age, multiple pregnancy, and other possible confounding factors, supporting that the role of these factors may be more relevant than the ART itself. The association between frozen embryo transfer and language delay has not been previously described. Thus, more studies are needed to confirm or refute this relationship.

EDA, EDAR, EDARADD and WNT10A allelic variants in patients with ectodermal derivative impairment in the Spanish population.

BACKGROUND: Ectodermal dysplasias (ED) are a group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives. An attenuated phenotype is considered a non-syndromic trait when the patient is affected by only one impaired ectodermal structure, such as in non-syndromic tooth agenesis (NSTA) disorder. Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common subtype, with an incidence of 1/50,000-100,000 males, and is associated with the EDA gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (2q13) and EDARADD (1q42.3) genes, respectively. The WNT10A gene (2q35) is associated more frequently with NSTA. Our goal was to determine the mutational spectrum in a cohort of 72 Spanish patients affected by one or more ectodermal derivative impairments referred to as HED (63/72) or NSTA (9 /72) to establish the prevalence of the allelic variants of the four most frequently associated genes. Sanger sequencing of the EDA, EDAR, EDARADD and WNT10A genes and multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: A total of 61 children and 11 adults, comprising 50 males and 22 females, were included. The average ages were 5.4 and 40.2 years for children and adults, respectively. A molecular basis was identified in 51/72 patients, including 47/63 HED patients, for whom EDA was the most frequently involved gene, and 4/9 NSTA patients, most of whom had variants of WNT10A. Among all the patients, 37/51 had variants of EDA, 8/51 had variants of the WNT10A gene, 4/51 had variants of EDAR and 5/51 had variants of EDARADD. In 42/51 of cases, the variants were inherited according to an X-linked pattern (27/42), with the remaining showing an autosomal dominant (10/42) or autosomal recessive (5/42) pattern. Among the NSTA patients, 3/9 carried pathogenic variants of WNT10A and 1/9 carried EDA variants. A total of 60 variants were detected in 51 patients, 46 of which were different, and out of these 46 variants, 12 were novel. CONCLUSIONS: This is the only molecular study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in HED and 44.4% in NSTA. Twelve novel variants were identified. The WNT10A gene has been confirmed as the second molecular candidate that has been identified and accounts for one-half of non-EDA patients and one-third of NSTA patients. Further studies using next generation sequencing (NGS) will help to identify other contributory genes in the remaining uncharacterized Spanish patients.

TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.

The redox state of the neural progenitors regulates physiological processes such as neuronal differentiation and dendritic and axonal growth. The relevance of endoplasmic reticulum (ER)-associated oxidoreductases in these processes is largely unexplored. We describe a severe neurological disorder caused by bi-allelic loss-of-function variants in thioredoxin (TRX)-related transmembrane-2 (TMX2); these variants were detected by exome sequencing in 14 affected individuals from ten unrelated families presenting with congenital microcephaly, cortical polymicrogyria, and other migration disorders. TMX2 encodes one of the five TMX proteins of the protein disulfide isomerase family, hitherto not linked to human developmental brain disease. Our mechanistic studies on protein function show that TMX2 localizes to the ER mitochondria-associated membranes (MAMs), is involved in posttranslational modification and protein folding, and undergoes physical interaction with the MAM-associated and ER folding chaperone calnexin and ER calcium pump SERCA2. These interactions are functionally relevant because TMX2-deficient fibroblasts show decreased mitochondrial respiratory reserve capacity and compensatory increased glycolytic activity. Intriguingly, under basal conditions TMX2 occurs in both reduced and oxidized monomeric form, while it forms a stable dimer under treatment with hydrogen peroxide, recently recognized as a signaling molecule in neural morphogenesis and axonal pathfinding. Exogenous expression of the pathogenic TMX2 variants or of variants with an in vitro mutagenized TRX domain induces a constitutive TMX2 polymerization, mimicking an increased oxidative state. Altogether these data uncover TMX2 as a sensor in the MAM-regulated redox signaling pathway and identify it as a key adaptive regulator of neuronal proliferation, migration, and organization in the developing brain.

High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor.

BACKGROUND: Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10-20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; CYP3A4*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669_698del30. RESULTS: AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype. CONCLUSIONS: AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.

New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.