Spanish Family Research Articles

Evidence for pathogenicity in a family with CADASIL

This article discusses the diagnosis of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) in a Spanish family through clinical data, electron microscopy of skin biopsy, and genetic analysis of the NOTCH3 gene. Two mutations were identified in the family members through the next generation sequencing of the NOTCH3 gene: c.1241C>G and c.3421G>A. The first was previously reported and associated with CADASIL in the Korean population and classified as VUS. This study provides further scientific evidence to reclassify this variant from VUS to pathogenic. The other variant was classified as a variant of uncertain clinical significance. The importance of analyzing the functional combination of different variants in the same gene in families with patients displaying different phenotypes is highlighted.

A Spanish Family with Gordon Syndrome Due to a Variant in the Acidic Motif of WNK1.

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS.

Family firms types based on beliefs

The purpose of this study was to find an effective way of identifying homogeneous family firm groups, based on the prevailing beliefs of the owning family on ownership, management and intergenerational transmission. We conducted a two-stage cluster analysis, using data from a representative sample of 240 Spanish family firms. The results showed three types of clearly differentiated family firms, each of them with a profile of different beliefs. Our work contributes to the previous literature by integrating the components of involvement and essence approaches and beliefs about these to distinguish homogeneous groups of family firms.

Morphological Hallmarks of Classical Fabry Disease: An Ultrastructural Study in a Large Spanish Family.

Fabry disease (FD) is a rare lysosomal disorder caused by α-galactosidase A deficiency, and it leads to the systemic deposition of globotriasylceramide. Demonstrations of the storage material in biopsies support this diagnosis. We report a histological and ultrastructural study of biopsies that were performed on 11 individuals from a family with the variant p.Gln279Arg in GLA, which is associated with the classical phenotype of Fabry disease. Intralysosomal deposits were found in all biopsies, corresponding to the skin, kidney, and endomyocardium in both sexes and at different ages. In nine of the skin biopsies, deposits were analysed by immunofluorescence and quantified at the ultrastructural level. Then, the findings were compared according to sex, genotype, and treatment. The quantification of the deposits in the skin biopsies revealed a broader involvement in men than in women. A significant clearance of the deposits was observed in one case after treatment. Tissue involvement was remarkable at diagnosis in all individuals. The findings from the skin biopsies were demonstrative of classic FD, thus supporting the diagnosis; repeated biopsy analyses suggested the benefit of early treatment.

“Tú sabes lo que le pasa a él?”: the Role of (Relational) Epistemics in Indirect Complaint Sequences in Spanish and English Family Talk

Abstract Drawing on interactional pragmatics and membership categorisation analysis, this paper explores indirect (third-party-oriented and situation-oriented) complaints in Spanish and English interactions between family members where expectations of affiliation are contingent on (relational) epistemic (im)balances. We analyse how (1) disaffiliation is constructed through the recipient’s more knowledgeable position in relation to the matter at hand, (2) complainability is legitimised when the recipient lacks epistemic access to the issue and (3) complaints are partially disattended by the recipient due to their inferior epistemic status regarding the situation. Throughout, we argue that (relational) epistemics is a necessary feature to incorporate in analysis, when it concerns the recipient’s responses and, therefore, interpersonal achievement of social actions. We show how complainants treat the prior turns as relevant to the rights, obligations and expectations related to their relational categories and how extended sequences of complaints are co-constructed and negotiated in interaction.

Gender diversity and collaboration with universities: drivers of innovation in family firms

PurposeThis paper provides empirical evidence for how gender diversity in top management teams (TMTs) and collaboration with university and technological centres lead to innovation outcomes. The authors review past research on these concepts and illustrate their individual and joint effects on process innovation specifically in the unique context of family firms (FFs).Design/methodology/approachThe authors used a sample of 788 Spanish manufacturing family firms in 2016 and applied logistic regression models since the dependent variables are dummies.FindingsThe authors found a positive relationship between gender-diverse TMTs, process innovation and research and development (R&D)-based process innovation. Similarly, the collaboration with university technological centres is positively associated with higher innovation outcome of FFs. In addition, the authors also found that the presence of women in TMTs shapes the relationship between the collaboration with university technological centres and process innovation.Originality/valueThis paper contributes to the research on collaborative innovation in FFs by emphasizing the collaboration with university technological centres, an external partner often ignored by this stream of literature. This research also responds to the calls for further study of the effect of the heterogeneity of the TMTs on the innovation outcome of FFs, from the perspective of the resource-based view (RBV) of the firms.

Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants.

Non-syndromic sensorineural hearing loss (SNHL) is the most common sensory disorder, and it presents a high genetic heterogeneity. As part of our clinical genetic studies, we ascertained a novel mutation in CCDC50 (c.828_858del, p.(Asp276Glufs*40)) segregating with the hearing impairment in a Spanish family with autosomal dominant DFNA44 SNHL that is predicted to disrupt the protein function. To gain insight into the mechanism behind DFNA44 mutations, we analysed two Ccdc50 presumed loss-of-function mouse mutants which showed normal hearing thresholds up to 6 months old, thus indicating that haploinsufficiency is unlikely to be the pathogenic mechanism. We then carried out in vitro studies on a set of artificial mutants and on the p.(Asp276Glufs*40) and p.(Phe292Hisfs*37) human mutations, and determined that only the mutants containing the six amino acid sequence CLENGL as part of their aberrant protein tail showed an abnormal distribution consisting of perinuclear aggregates of the CCDC50-encoded protein Ymer. Therefore, we conclude that the CLENGL sequence is necessary to form the aggregates. Taken together the in vivo and in vitro results obtained in this study suggest that the two Spanish mutations in CCDC50 exert their effect through a dominant-negative or gain of function mechanism rather than by haploinsufficiency.

The Origins of the Royal Spanish Surname Castilla: Genetics and Genealogy

In most Western European societies, surnames pass from generation to generation and in cases where surnames are shared by fathers to children, the Y chromosome passes down from fathers to male offspring in the same way as surnames do. The aim of this study was to ascertain the patrilineal relationship between individuals with the surname “Castilla” and their respective Y-chromosome haplotypes. The toponymic surname “Castilla” is part of the Spanish royal family. Genealogical studies of this surname have allowed the formulation of different hypotheses about its origin, most of which were centered in Burgos. To shed some light on the origin of the surname Castilla and to investigate the possible co-ancestry behind the living carriers of this surname, markers located in the Y chromosome-specific region were analyzed in a sample of 102 men whose paternal surname was Castilla. The study aimed to establish the minimum number of founders and the expansion time of the lineages from our sample. Two major haplogroups were identified: R1b and E1b1b-M81. The high frequency of the E1b1b-M81 haplogroup in comparison to that of the general Spanish population, its low haplotype diversity, and its young TMRCA (323+/− 255 years CE) are compatible with the historical timing of the obligation to use surnames. However, the coincidence of the most common haplogroup in the Castilla sample and the most frequent haplogroup in the Spanish general population, R1b, makes it difficult to identify founder haplotypes/haplogroups in the history of the Castilla surname.

Dynamic capabilities and environmental performance: all in the family

PurposeThis study adopts the dynamic capabilities perspective to analyze environmental performance in family firms and explores the moderating effects that both family involvement in the Top Management Team (TMT) and long-term orientation (LTO) exert on the relationship between dynamic capabilities and environmental performance.Design/methodology/approachThe authors test the hypotheses on a database of 748 family tourism firms, using hierarchical regression analysis.FindingsThe authors' results show that both variables have a beneficial effect on building the dynamic capabilities to be applied to improving environmental performance. However, the moderating effect of family involvement is revealed to be more complex than that of LTO. Having a high degree of family managerial involvement positively moderates the effect of dynamic capabilities on environmental performance but only in family firms with highly-developed dynamic capabilities; conversely, in family firms with lower levels of dynamic capabilities not having this family involvement in the TMT is better.Originality/valueThis study helps advance the research on Spanish family tourism firms by adopting an approach that unveils the heterogeneity in dynamic capabilities among said firms, driven by the firms' idiosyncratic features in terms of family involvement in the TMT and their LTO. The article also provides practical insights for family business owners, managers and advisors and outlines important directions for future research.

Psychological impact of six weeks of strict home confinement in Spanish families having school-aged children with attention-deficit/hyperactivity disorder

After the COVID-19 outbreak, early publications reported worsening symptoms and increased caregiver burden in families having children with Attention-Deficit/Hyperactivity Disorder (ADHD). In the present study, we launched an online survey to examine the psychological impact of the 41 days of strict home confinement implemented in Spain in families having children with ADHD compared to families having children with typical development (TD). We achieved a representative sample of 190 school-aged children (NADHD =100 and NTD=90) from 181 families. Respondents were mainly mothers (≈96%). We found that mother reports of hyperactive-impulsive symptoms significantly increased during home confinement regardless of ADHD diagnosis. During the lockdown, we also found that perceived stress significantly increased in mothers of ADHD and TD children, but, unexpectedly, this increase was much more noticeable for the latter group. Moreover, our study suggests that children having parents working in frontline jobs or living in families with higher household conflicts might display increased ADHD symptoms during the lockdown, irrespective of ADHD diagnosis. Our results highlight the need to provide psychological support to families most exposed to the pandemic and target household problems and mothers’ well-being at intervention processes, in both ADHD and TD families.

Catastrophic out-of-pocket payments for dental treatment: regional evidence from Spain

BackgroundTo estimate the incidence and concentration of catastrophic out-of-pocket payments for healthcare and dental treatment, by region in Spain (calculated as the proportion of households needing to exceed a given threshold of their income to make these payments) in 2008, 2011 and 2015.MethodsThe data analysed were obtained from the Spanish Family Budget Survey reports for the years in question. The study method was that proposed by Wagstaff and van Doorslaer (2003), contrasting payments for dental treatment versus household income and considering thresholds of 10%, 20%, 30% and 40%, thus obtaining incidence rates. In addition, relevant sociodemographic variables were obtained for each household included in the study.ResultsWith some regional heterogeneity, on average 4.75% of Spanish households spend more than 10% of their income on dental treatment, and 1.23% spend more than 40%. Thus, 38.67% of catastrophic out-of-pocket payments for dental services in Spain corresponds to payments at the 10% threshold. This value rises to 55.98% for a threshold of 40%.ConclusionsAn important proportion of catastrophic out-of-pocket payments for health care in Spain corresponds to dental treatment, a service that has very limited availability under the Spanish NHS. This finding highlights the need to formulate policies aimed at enhancing dental cover, in order to reduce inequalities in health care and, consequently, enhance the population’s quality of life and health status.

Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts.

Non-syndromic pediatric cataracts are defined as opacification of the crystalline lens that occurs during the first years of life without affecting other organs. Given that this disease is one of the most frequent causes of reversible blindness in childhood, the main objective of this study was to propose new responsible gene candidates that would allow a more targeted genetic approach and expand our genetic knowledge about the disease. We present a whole exome sequencing (WES) study of 20 Spanish families with non-syndromic pediatric cataracts and a previous negative result on an ophthalmology next-generation sequencing panel. After ophthalmological evaluation and collection of peripheral blood samples from these families, WES was performed. We were able to reach a genetic diagnosis in 10% of the families analyzed and found genes that could cause pediatric cataracts in 35% of the cohort. Of the variants found, 18.2% were classified as pathogenic, 9% as likely pathogenic, and 72.8% as variants of uncertain significance. However, we did not find conclusive results in 55% of the families studied, which suggests further studies are needed. The results of this WES study allow us to propose LONP1, ACACA, TRPM1, CLIC5, HSPE1, ODF1, PIKFYVE, and CHMP4A as potential candidates to further investigate for their role in pediatric cataracts, and AQP5 and locus 2q37 as causal genes.

BG01 Confirming small nuclear ribonucleoprotein polypeptide E as a cause of nonsyndromic hypotrichosis

Abstract Hereditary nonsyndromic hypotrichosis comprises at least 15 genetically distinct but phenotypically overlapping disorders. Affected individuals generally have hair at birth, which sheds during infancy or childhood. Severity ranges from partial alopecia to complete loss of scalp and body hair, with phenotypic variability between and within families. Genetic testing is essential for accurate diagnosis and counselling. We describe a case where several factors contributed to a delay in genetic diagnosis. A female child of nonconsanguineous White parents was born at term with normal hair that started to shed at 2 weeks of age. By 6 weeks of age, there was a complete absence of scalp, eyelash and eyebrow hair. There was no relevant family history apart from atopy. On examination at 3.3 years of age, she had total alopecia apart from some hairs in the external auditory canals. Nails, teeth and sweating were normal. She appeared developmentally normal and healthy apart from mild eczema with persistent erythema on both cheeks. The differential diagnosis included autoimmune alopecia and genetic nonsyndromic hypotrichosis. She was recruited to the 100 000 Genomes Project, but primary analysis did not identify any causative variants. Reanalysis using a limited gene-agnostic approach identified heterozygosity for the c.1A>G; p.(Met1?) variant in small nuclear ribonucleoprotein polypeptide E (SNRPE) that was not present in parents. This variant is not present in the gnomAD population database and is predicted to alter the initiation codon of SNRPE. It has been reported de novo in a British girl with sparse scalp hair and eyelashes and absent eyebrows, and in eight affected members of a Spanish family whose phenotypes ranged from sparse eyebrows and eyelashes to complete alopecia (Pasternack SM, Refke M, Paknia E et al. Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal dominant hypertrichosis simplex. Am J Hum Genet 2013; 92:81–7). This condition has been designated hypotrichosis type 11. SNRPE encodes a core protein of U small nuclear ribonucleoproteins, which are essential to the removal of introns from pre-mRNA and thus critical for the post-transcriptional modification of RNA. In our case, review of the primary analysis showed that the incorrect gene panel was applied (‘familial cicatricial alopecia’ instead of ‘nonsyndromic hypotrichosis’) and that SNRPE was listed as ‘amber’ for hypotrichosis, meaning ‘moderate evidence for this gene–disease association and should not yet be used for genome interpretation’. Genomics England has now incorporated nonsyndromic hypotrichosis into the ‘ectodermal dysplasia’ panel, with SNRPE now listed as ‘green’ for hypotrichosis 11, meaning a ‘high level of evidence for this gene–disease association’. This case emphasizes the importance of revisiting negative results as knowledge evolves.

Parental competences in fathers and mothers of very‐low‐birth‐weight preterm infants

AbstractObjectiveThe goal was to analyze parental competences in Spanish families with very‐low‐birth‐weight infants (≤32 weeks and/or less 1500 g) over 18 months of corrected age.BackgroundParenting in families of very preterm infants is an interesting focus of research as we advance in the knowledge of how parental competences can have an important impact on child development.MethodSixty‐eight mothers and 56 fathers completed measures of parental competences, sociofamily risk, parental stress, social support, and emotional symptoms. Clinical characteristics and neonatal medical risk data were collected after birth. Statistical analyses were performed to compare parental competences with those of mothers and fathers of non‐preterm infants. Generalized estimating equations were used for analysis, adjusted by family unit.ResultsMothers and fathers of preterm infants score higher in most dimensions of parental competences compared to a control group. Focusing on the preterm population, mothers score higher than fathers in daily involvement and mentalization and lower in parental self‐care. When studied separately, we found different scores for fathers and mothers in parental competences (sociofamily risk, parental stress, social support, and emotional symptoms).ConclusionParents of preterm infants present better parental competences than parents of non‐preterm infants when their children reach 18 months of age. It is important to consider the differences in parental competences between the mothers and fathers of these children.ImplicationsOur findings suggest the need to address parental competences to develop preventive and adaptive strategies in parents of preterm infants to promote positive parenting.

Psychological wellbeing in adult adoptees: current age and developmental tasks.

Studies about adult adoptees are normally focused on the differences in adjustment difficulties between them and non-adoptees. However, there has been less research about adoptees' positive and developmental adjustment in adulthood. The aim of this study is to test a model of the mediating role of adoptees' achievement of adulthood tasks in the relationship between current age and psychological wellbeing. The sample consisted of 117 adults who were adopted as children by Spanish families. Their current mean age is 28.3 years. Participants underwent an interview and completed Ryff's Psychological WellBeing Scales. Findings show that current age is directly and negatively related to psychological wellbeing [c' = -0.039, 95% CI (-0.078, -0.001)], and the relationship between these variables is mediated by adoptees' achievement of adulthood tasks [indirect effect = 0.035, 95% CI (.014, 0.059)]. The findings support traditional theories about transitioning to adulthood, and adds relevant information about this transition in adoptees. Moreover, this work indicates a new way of assessing adoption success, based on long-term measures and normative variables. Services providers should account for the importance of supporting young people on their life transitions and promoting their wellbeing, especially among those who started from disadvantaged contexts.

Genetic linkage analysis of head and neck cancer in a Spanish family.

To describe the genetic variants that may be associated with the development of head and neck cancer (HNC) and functionally validating the molecular implications. A prospective observational study was carried out on a family of 3 generations in which 3 members had developed HNC. Peripheral blood sample was taken in a routine procedure for exome sequencing in one relative and genotyping in the remaining twelve relatives. For the functional analysis all-trans retinoic acid (atRA) was extracted from saliva and serum and measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The presence of HPV-DNA. None of the patients smoked or consumed alcohol. The presence of HPV DNA was not detected in any of the biopsied samples. A total amount of 6 members out of 13 (46.15%) carried out the same mutation of CYP26B1 (2p13.2; G>T). The mean plasma concentration of atRA was 3.3109 ± 1.4791 pg/mL for the study family and 4.7370 ± 1.5992 pg/mL for the controls (p = 0.042). Lower levels of atRA were confirmed in the study family, which may open the way to the possible relationship between the polymorphism CYP26B1 (2p13.2; G>T) and HNC.

Identification of Novel Candidate Genes for Familial Thyroid Cancer by Whole Exome Sequencing.

Thyroid carcinoma (TC) can be classified as medullary (MTC) and non-medullary (NMTC). While most TCs are sporadic, familial forms of MTC and NMTC also exist (less than 1% and 3-9% of all TC cases, respectively). Germline mutations in RET are found in more than 95% of familial MTC, whereas familial NMTC shows a high degree of genetic heterogeneity. Herein, we aimed to identify susceptibility genes for familial NMTC and non-RET MTC by whole exome sequencing in 58 individuals belonging to 18 Spanish families with these carcinomas. After data analysis, 53 rare candidate segregating variants were identified in 12 of the families, 7 of them located in previously TC-associated genes. Although no common mutated genes were detected, biological processes regulating functions such as cell proliferation, differentiation, survival and adhesion were enriched. The reported functions of the identified genes together with pathogenicity and structural predictions, reinforced the candidacy of 36 of them, suggesting new loci related to TC and novel genotype-phenotype correlations. Therefore, our strategy provides clues to possible molecular mechanisms underlying familial forms of MTC and NMTC. These new molecular findings and clinical data of patients may be helpful for the early detection, development of tailored therapies and optimizing patient management.

New ZNF469 Mutations in Spanish Siblings With Brittle Cornea Syndrome.

The aim of this study was to describe the clinical, tomographic, and genetic findings of 2 Spanish siblings with brittle cornea syndrome and report a new mutation of gene ZNF469 implicated in the development of this disorder. In this study, 2 male siblings who had been diagnosed with brittle cornea syndrome underwent ophthalmologic and genetic assessment. A novel homozygous deletion c.2972del, p.(Pro991Hisfs62) in the ZNF469 gene was identified in a Spanish family. This is the first report of a ZNF469 mutation in a Spanish family causing brittle cornea syndrome. The discovery of this new mutation amplifies the spectrum of ZNF469 variants implicated in this syndrome.

Family Functioning as an Explanatory Factor of Empathic Behavior in Argentine Medical Students.

Ex post facto design: 306 Argentine medical students who had already taken the Jefferson Scale of Empathy-Spanish Edition (JSE-S) and the abbreviated Spanish Family Adaptability and Cohesion Evaluation Scale (FACES-20). A gender-weighted linear regression analysis was made, establishing an ANOVA and multiple comparisons via DMS to determine the effect of functional and dysfunctional families' balanced, intermediate and extreme functioning styles concerning empathy. Students who presented dysfunction in familial cohesion and adaptability showed measures of empathy greater than those classified as functional. Differences of cohesion were statistically significant in compassionate care, perspective taking and general empathy. These components were significantly higher in students from families classified as extreme than balanced ones. Students classified within families with either extreme or dysfunctional styles showed greater levels of empathy than more adaptive and functional ones, except in the 'walking in patient's shoes' component where differences were not observed. Individual resilience as an intervening variable in the presence of empathy is discussed. The study of empathy, its associated variables, and the conditions of its development remains a central theme in relation to students and professionals of the health sciences. To achieve an effective professional practice, it is necessary to develop human capacities such as empathy and personal resilience.

Knowledge integration in family firms: Understanding the nexus between familiness and organizational effectiveness

AbstractAlthough knowledge integration has been deemed relevant for the development and survival of family firms, prior studies suggest that the lack of skills to combine and transfer incumbent family members' knowledge within the family may hinder family firms' organizational effectiveness. Knowledge integration, in this context, might depend on family involvement in ownership, management and governance, and family essence, considering the emotional and relational aspects of the influence the family exerts on the business. Relying on knowledge‐based view and dynamic capability perspectives, we propose a model suggesting that knowledge integration intervenes in the relationship between familiness and organizational effectiveness. Our hypotheses are tested on a sample of 102 private Spanish family businesses. The results reveal that familiness is beneficial for knowledge integration, enhancing family firms' organizational effectiveness. Our study provides practical implications for family business owners and managers, and opportunities for further research.