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.

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

A Novel Mutation Associated with Neonatal Lethal Cardiomyopathy Leads to an Alternative Transcript Expression in the X-Linked Complex I NDUFB11 Gene.

We report a neonatal patient with hypertrophic cardiomyopathy (HCM), lactic acidosis and isolated complex I deficiency. Using a customized next-generation sequencing panel, we identified a novel hemizygous variant c.338G>A in the X-linked NDUFB11 gene that encodes the NADH: ubiquinone oxidoreductase subunit B11 of the mitochondrial respiratory chain (MRC) complex I (CI). Molecular and functional assays performed in the proband's target tissues­skeletal and heart muscle­showed biochemical disturbances of the MRC, suggesting a pathogenic role for this variant. In silico analyses initially predicted an amino acid missense change p.(Arg113Lys) in the NDUFB11 CI subunit. However, we showed that the molecular effect of the c.338G>A variant, which is located at the last nucleotide of exon 2 of the NDUFB11 gene in the canonical 'short' transcript (sized 462 bp), instead causes a splicing defect triggering the up-regulation of the expression of an alternative 'long' transcript (sized 492 bp) that can also be detected in the control individuals. Our results support the hypothesis that the canonical 'short' transcript is required for the proper NDUFB11 protein synthesis, which is essential for optimal CI assembly and activity, whereas the longer alternative transcript seems to represent a non-functional, unprocessed splicing intermediate. Our results highlight the importance of characterizing the molecular effect of new variants in the affected patient's tissues to demonstrate their pathogenicity and association with the clinical phenotypes.

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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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)

Clinical features and health-related quality of life in adult patients with mucopolysaccharidosis IVA: the Spanish experience.

BACKGROUND: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). RESULTS: Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5-40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106-136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03-2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68-3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25-2.34) versus 2.25 (1.62-3.00) in patients not treated with ERT. CONCLUSIONS: The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.

[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.

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.

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.

Further refinement of COL4A1 and COL4A2 related cortical malformations.

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia. METHODS: We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly. RESULTS: One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations. CONCLUSIONS: Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.

A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases.

Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.