Genetic and Environmental Influences on Optimism and its Relationship to Mental and Self-Rated Health: A Study of Aging Twins

Optimism has been shown to be important in maintaining wellbeing into old age, but little is known about the sources of variation in optimism and its links to mental and somatic health. Optimism, mental, and self-rated health were measured in 3,053 twin individuals (501 MZF, 153 MZM, 274 DZF, 77 DZM, and 242 DZ opposite-sex twin pairs and 561 single twins) over 50 years using the life orientation test, the General Health Questionnaire and a single-item question for self-rated health. Additive genetic factors explained 36, 34, and 46% of the variation in optimism, mental, and self-rated health, respectively, with the remainder being due to non-shared environmental influences. Genetic influences accounted for most of the covariance between the variables (14–20% of the genetic variance) indicating that in older adults genes predisposing to high optimism also predispose to good mental health and self-rated health.     

Clinical utility of the X‐chromosome array

Previous studies have limited the use of specific X‐chromosome array designed platforms to the evaluation of patients with intellectual disability. In this retrospective analysis, we reviewed the clinical utility of an X‐chromosome array in a variety of scenarios. We divided patients according to the indication for the test into four defined categories: (1) autism spectrum disorders and/or developmental delay and/or intellectual disability (ASDs/DD/ID) with known family history of neurocognitive disorders; (2) ASDs/DD/ID without known family history of neurocognitive disorders; (3) breakpoint definition of an abnormality detected by a different cytogenetic test; and (4) evaluation of suspected or known X‐linked conditions. A total of 59 studies were ordered with 27 copy number variants detected in 25 patients (25/59 = 42%). The findings were deemed pathogenic/likely pathogenic (16/59 = 27%), benign (4/59 = 7%) or uncertain (7/59 = 12%). We place particular emphasis on the utility of this test for the diagnostic evaluation of families affected with X‐linked conditions and how it compares to whole genome arrays in this setting. In conclusion, the X‐chromosome array frequently detects genomic alterations of the X chromosome and it has advantages when evaluating some specific X‐linked conditions. However, careful interpretation and correlation with clinical findings is needed to determine the significance of such changes. When the X‐chromosome array was used to confirm a suspected X‐linked condition, it had a yield of 63% (12/19) and was useful in the evaluation and risk assessment of patients and families. © 2012 Wiley Periodicals, Inc.     

Cutaneous clues for diagnosing X‐chromosomal disorders

In a multidisciplinary outpatient clinic for hereditary skin diseases and/or syndromes involving the skin, 7% (30 of 409) of patients were found to have an abnormality involving the X chromosome, a mutation in a gene located on the X chromosome or a clinical diagnosis of an X‐linked monogenetic condition. The collaboration of a dermatologist and a clinical geneticist proves to be very valuable in recognizing and diagnosing these conditions. By combining their specific expertize in counselling an individual patient, X‐linked diagnoses were recognized and could be confirmed by molecular and/or cytogenetic studies in 24 of 30 cases. Mosaicism plays an important role in many X‐linked hereditary skin disorders. From our experience, we extracted clinical clues for specialists working in the field of genetics and/or dermatology for considering X‐linked disorders involving the skin.     

Exome sequencing of sporadic childhood‐onset schizophrenia suggests the contribution of X‐linked genes in males

Childhood‐onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole‐exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X‐linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X‐linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X‐linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.     

Identification of Intellectual Disability Genes in Female Patients with a Skewed X‐Inactivation Pattern

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X‐linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X‐inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X‐inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole‐exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X‐inactivation presumably cause both XLID and skewing of X‐inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients.     

Maladaptive schemas in non‐clinical adolescents: relations to perceived parental rearing behaviours,Big Five personality factors and psychopathological symptoms

The current study examined Jeffrey Young's (1994) maladaptive schemas in a sample of 173 non‐clinical adolescents aged between 12 and 15 years. Participants completed an age‐downward version of the Young Schema Questionnaire as well as self‐report scales to assess perceptions of parental rearing behaviours, personality traits and psychopathological symptoms. Results indicated that detrimental rearing behaviours were associated with the presence of maladaptive schemas. Further, the personality trait of neuroticism was positively related to a broad range of maladaptive schemas. Some evidence was found indicating that neuroticism and detrimental parental rearing behaviours both accounted for a unique proportion of the variance in distorted thinking patterns. Finally, maladaptive schemas were linked to various types of psychological symptoms, including symptoms of anxiety disorders, depression, disruptive behaviour, eating problems and substance use. Altogether, these findings are well in line with Young's theory and seem to warrant more research on maladaptive schemas in young people. Copyright © 2006 John Wiley & Sons, Ltd.     

X‐linkage does not account for the absence of father–son similarity in plasma uric acid concentrations

Plasma uric acid concentration aggregates in families, and this similarity has been suggested to be due, in part, to multiple shared genes. Men have higher plasma uric acid concentrations than women and are affected with gout nine times more frequently. Rare forms of hyperuricemia and gout are due to mutations of X‐linked genes (HPRT1 and PRPS1). Given these observations, we tested the hypothesis that normal variation in plasma uric acid levels would display a pattern of familial similarity consistent with X‐linkage in 892 individuals from 196 obese but otherwise healthy families. As predicted by X‐linked inheritance, fathers and sons showed no resemblance in plasma uric acid concentration (r = 0.013, NS), while all other pairings showed moderate‐to‐strong familial resemblance (ranging from 0.167, P < 0.01, parent–offspring to 0.415, sister–sister, P < 0.01). We then tested the hypothesis that loci along the X chromosome would influence plasma uric acid concentration. We conducted both single‐point and multipoint linkage analyses using 17 X‐linked markers spaced at approximately 9 cm intervals to determine whether allele sharing among sibs was related to sib similarity in plasma uric acid concentrations (n = 1,100 sib pairs). We found no regions of the X chromosome that cosegregated with plasma uric acid concentrations (P > 0.05). We conclude that variation in genes on the X chromosome contribute little to normal variation in plasma uric acid concentrations. Am. J. Med. Genet. 92:142–146, 2000. © 2000 Wiley‐Liss, Inc.     

Genes that escape from X‐chromosome inactivation: Potential contributors to Klinefelter syndrome

One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X‐linked genes between XX females and XY males. Not all X‐linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X‐chromosome inactivation and discuss the nature of their sex‐biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y‐chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.     

X‐linked intellectual disability update 2017

The X‐chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X‐linked intellectual disability (XLID)‐associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high‐throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high‐resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function.     

Female factor IX deficiency due to maternally inherited X‐inactivation

Esquilin JM, Takemoto CM, Green, NS. Female factor IX deficiency due to maternally inherited X‐inactivation. X‐chromosome inactivation is normally a random event that is regulated by the X chromosome itself. Rarely, females are affected by X‐linked disorders from extremely skewed X‐chromosome inactivation. Here, we report a family with hemophilia B with female expression through inherited X skewing that appears to be independent of either X chromosome. This finding suggests the possibility of a dominant autosomal contribution to inherited skewed X inactivation.     

A novel pathogenic variant in OFD1 results in X‐linked Joubert syndrome with orofaciodigital features and pituitary aplasia

Orofaciodigital syndrome type I and X‐linked recessive Joubert syndrome are known ciliopathic disorders that are caused by pathogenic variants in OFD1 gene. Endocrine system involvement with these conditions is not well described. We present the first report of a newborn male with a novel hemizygous variant in OFD1 gene c.515T>C, (p.Leu172Pro) resulting in X‐linked Joubert syndrome and orofaciodigital features with complete pituitary gland aplasia and subsequent severe hypoplasia of peripheral endocrine glands. This clinical report expands the phenotypic spectrum of endocrine system involvement in OFD1‐related disorders and suggests that OFD1 gene may be related to pituitary gland development.     

Osteopathia striata cranial sclerosis: Non‐random X‐inactivation suggestive of X‐linked dominant inheritance

Osteopathia striata with cranial sclerosis (OS‐CS) is a rare syndrome comprising macrocephaly, minor anomalies, conductive hearing loss, and mild mental retardation. The diagnosis is based on radiological findings, including cranial sclerosis and longitudinal striations of metaphyses of long bones. Here we report on 10 new cases of OS‐CS, including two sporadic cases and three families, with an excess of affected females (9F/1M). Phenotypic variability was observed in our patients as well as several unusual findings. Hirschsprung disease, Pierre Robin sequence, coronal craniostenosis, and laryngotracheomalacia were associated with a poor prognosis. The X‐inactivation pattern of peripheral blood lymphocytes in a mildly affected mother and her severely affected boy demonstrated a non‐random X‐inactivation in the mother. This finding, in combination with a sex ratio in favor of females and an increased morbidity and mortality in males, is highly suggestive of X‐linked dominant inheritance. © 2001 Wiley‐Liss, Inc.     

A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X‐Linked Intellectual Disability,Cerebellar Hypoplasia,and Spondylo‐Epiphyseal Dysplasia

RPL10 encodes ribosomal protein L10 (uL16), a highly conserved multifunctional component of the large ribosomal subunit, involved in ribosome biogenesis and function. Using X‐exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N‐terminal domain of the protein, in a family with two affected cousins presenting with X‐linked intellectual disability, cerebellar hypoplasia, and spondylo‐epiphyseal dysplasia (SED). We assessed the impact of the mutation on the translational capacity of the cell using yeast as model system. The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10. However, unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population. Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders.     

Phenotypic heterogeneity and mutational spectrum in a cohort of 45 Italian males subjects with X‐linked ectodermal dysplasia

Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal‐derived structures. X‐linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal‐derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.     

Genetic heterogeneity of syndromic X‐linked recessive microphthalmia‐anophthalmia: Is Lenz microphthalmia a single disorder?

Nonsyndromic congenital microphthalmia or anophthalmia is a heterogeneous malformation with autosomal dominant, autosomal recessive, and X‐linked modes of inheritance. Lenz microphthalmia syndrome comprises microphthalmia with mental retardation, malformed ears, skeletal anomalies, and is inherited in an X‐linked recessive pattern. Prior studies have shown linkage of both isolated (or nonsyndromic) anophthalmos (ANOP1, [MIM 301590]) and Lenz syndrome [MIM 309800] to Xq27–q28. Nonsyndromic colobomatous microphthalmia [MIM 300345] has been linked to Xp11.4–Xq11.1. We describe a five‐generation African‐American family with microphthalmia or anophthalmia, mental retardation, and urogenital anomalies, in an X‐linked recessive inheritance pattern, consistent with Lenz syndrome. Initial linkage analysis with microsatellite markers excluded the region in Xq27–q28 previously reported as a candidate region for ANOP1 [MIM 301590]. An X‐chromosome scan revealed linkage to a 10‐cM region between markers DXS228 and DXS992 in Xp11.4–p21.2. Multipoint analysis gave a maximum LOD score of 2.46 at marker DXS993. These data show that X‐linked recessive syndromic microphthalmia exhibits genetic heterogeneity. In addition, it suggests that Lenz microphthalmia syndrome, previously thought to be a single disorder, may represent an amalgam of two distinct disorders. © 2002 Wiley‐Liss, Inc.     

X‐chromosomal inactivation directly influences the phenotypic manifestation of X‐linked protoporphyria

X‐linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain‐of‐function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X‐linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X‐chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc‐finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X‐chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild‐type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin‐containing peripheral blood fluorocytes. When the wild‐type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP.     

Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability,macrocephaly, and obesity: A series of 17 patients

BRWD3 has been described as a cause of X‐linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth‐intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.     

Copy number of the X‐linked genes TLR7 and CD40L influences innate and adaptive immune responses

The number of the X chromosome–linked genes has been previously suggested to influence immune responses and the development of autoimmune diseases. In the present study, we aimed at evaluating the level of expression of CD40L (an X‐linked gene involved in adaptive immunity) and TLR7 (an X‐linked gene involved in innate immunity) in a variety of different karyotypes. Those included males, females and patients with X chromosome aneuploidy. Healthy females (46, XX; n = 10) and healthy males (46, XY; n = 10) were compared to females with Turner syndrome (TS) (45, X; n = 11) and males with Klinefelter syndrome (KS) (47, XXY; n = 5). Stimulation of peripheral blood mononuclear cells (PBMCs) with PMA and ionomycin resulted in higher percentage of CD3 + CD40L+ T cells (P < 0.001) and higher level expression of CD40L in T cell (P < 0.001) in female and KS patients compared with male and TS patients. TLR7‐mediated IFN‐alpha production by HLADR + CD3? CD19? cells was significantly upregulated in healthy women compared with healthy males, TS and KS patients (P < 0.001). TLR7 agonist‐stimulated PBMCs from healthy females and KS patients expressed significantly higher levels of TLR7 mRNA than those from male and TS patients (P < 0.05). The increased expression of the X‐linked genes TLR7 and CD40L in healthy females and KS patients suggests that the presence of two X chromosomes plays a major role in enhancing both innate and adaptive immune responses. These results may contribute to the explanation of sex‐based differences in immune biology and the sex bias in predisposition to autoimmune diseases.     

A report on state‐wide implementation of newborn screening for X‐linked Adrenoleukodystrophy

Minnesota became the fourth state to begin newborn screening (NBS) for X‐linked adrenoleukodystrophy (X‐ALD) in 2017. As there is limited retrospective data available on NBS for X‐ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0‐LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X‐ALD and all were subsequently confirmed to have X‐ALD, with zero false positives. The birth prevalence of X‐ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X‐ALD. Phenotypes of these family members included self‐reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X‐ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population‐based screening for X‐ALD.