Central Asia has served as a corridor for human migrations providing trading routes since ancient times. It has functioned as a conduit connecting Europe and the Middle East with South Asia and far Eastern civilizations. Therefore, the study of populations in this region is essential for a comprehensive understanding of early human dispersal on the Eurasian continent. Although Y- chromosome distributions in Central Asia have been widely surveyed, present-day Afghanistan remains poorly characterized genetically. The present study addresses this lacuna by analyzing 190 Pathan males from Afghanistan using high-resolution Y-chromosome binary markers. In addition, haplotype diversity for its most common lineages (haplogroups R1a1a*-M198 and L3-M357) was estimated using a set of 15 Y-specific STR loci. The observed haplogroup distribution suggests some degree of genetic isolation of the northern population, likely due to the Hindu Kush mountain range separating it from the southern Afghans who have had greater contact with neighboring Pathans from Pakistan and migrations from the Indian subcontinent. Our study demonstrates genetic similarities between Pathans from Afghanistan and Pakistan, both of which are characterized by the predominance of haplogroup R1a1a*-M198 (>50%) and the sharing of the same modal haplotype. Furthermore, the high frequencies of R1a1a-M198 and the presence of G2c-M377 chromosomes in Pathans might represent phylogenetic signals from Khazars, a common link between Pathans and Ashkenazi groups, whereas the absence of E1b1b1a2-V13 lineage does not support their professed Greek ancestry.
Afghanistan; Pathans/Pashtuns; Y-SNP; phylogenetic analyses; haplogroup; haplotype
Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neurodevelopmental disorders, we obtained volumetric measurements of the CC and its subregions, examined the relationship between these regions and neurocognition and selected genotypes within candidate genes in the 22q11.2 interval in 59 children with 22q11DS and 53 control subjects. The total CC, splenium and genu were significantly larger in children with 22q11DS and the enlargement was associated with better neurocognitive functioning in the 22q11DS group, suggestive of a compensatory increase in the CC volumes. The expected age-related increase in the volume of the CC was not seen in children with 22q11DS, indicative of dysmaturation of the CC in these children. The increased volumes in the genu, splenium and total CC in the 22q11DS group were associated with polymorphisms within the candidate genes: COMT (rs4680), ZDHHC8 (rs175174) and UFD1L (rs5992403). These findings indicate that alterations in the CC volume in children with 22q11DS are associated with cognition and specific genotypes in the 22q11.2 interval.
chromosome 22q11.2 deletion syndrome; velocardiofacial syndrome; corpus callosum; neurocognition; schizophrenia
Since the 1990s, many countries in Europe and the United States have enacted genetic non-discrimination legislation to prevent people from deferring genetic tests for fear that insurers or employers would discriminate against them based on that information. Although evidence for genetic discrimination exists, little is known about the origins and backgrounds of fears of discrimination and how it affects decisions for uptake of genetic testing. The aim of this article is to gain a better understanding of these fears and its possible impact on the uptake of testing by studying the case of hypertrophic cardiomyopathy (HCM). In a qualitative study, we followed six Dutch extended families involved in genetic testing for HCM for three-and-a-half years. Semi-structured interviews were conducted with 57 members of these families. Based on the narratives of the families, we suggest that fears of discrimination have to be situated in the broader social and life-course context of family and kin. We describe the processes in which families developed meaningful interpretations of genetic discrimination and how these interpretations affected family members' decisions to undergo genetic testing. Our findings show that fears of genetic discrimination do not so much stem from the opportunity of genetic testing but much more from earlier experiences of discrimination of diseased family members. These results help identify the possible limitations of genetic non-discrimination regulations and provide direction to clinicians supporting their clients as they confront issues of genetic testing and genetic discrimination.
genetic discrimination; fear; insurance; family experiences; hypertrophic cardiomyopathy
The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin–angiotensin–aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.
hypertrophic; cardiomyopathy; renin–angiotensin–aldisterone system; echocardiography
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, PSR and POR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant PSRP-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
anxiety; neuroticism; panic disorder; linkage; meta-analysis
As decreased bone mineral density (BMD) is a common problem in cystic fibrosis (CF) and milk products may have pivotal dietary role affecting BMD, we aimed to assess the potential influence of adult-type hypolactasia (ATH) and lactose malabsorption (LM) on BMD in adolescent and young adult patients. In 95 CF pancreatic-insufficient patients aged 10–25 years (without liver cirrhosis, steatosis and cholestasis, diabetes mellitus, systemic glucocorticoid therapy), lumbar BMD, the nutritional status, pulmonary function, vitamin D3 concentration, calcium intake and single-nucleotide polymorphism upstream of the lactase gene were assessed. In subjects with the −13910 C/C genotype predisposing to ATH, the presence of LM was determined with the use of a hydrogen–methane breath test (BT). BMD and calcium intake were significantly lower in patients with the C/C genotype (P<0.028 and P<0.043, respectively). The abnormal BMD was stated more frequently in patients with the C/C genotype (P<0.042) and with LM (P<0.007). BMD, daily calcium intake and serum vitamin D concentration were significantly lower in LM subjects than in the other patients (P<0.037, P<0.000004 and P<0.0038, respectively). In logistic regression analysis, the relationship between examined parameters and BMD, was found to be statistically significant (P<0.001). However, only standardized body weight and LM were documented to influence BMD (P<0.025 and P<0.044, respectively). In conclusion, LM seems to be an independent risk factor for decreased BMD in CF patients.
cystic fibrosis; bone mineral density; adult-type hypolactasia; lactose malabsorption
We present six patients from five unrelated families with a condition originally described by Van Maldergem et al and provide follow-up studies of the original patient. The phenotype comprises a distinctive facial appearance that includes blepharophimosis, maxillary hypoplasia, telecanthus, microtia and atresia of the external auditory meatus, intellectual disability, digital contractures and skeletal anomalies together with subependymal and subcortical neuronal heterotopia. Affected patients typically have neonatal hypotonia, chronic feeding difficulties and respiratory problems. In our cohort, we have observed one instance of sibling recurrence and parental consanguinity in three of the families, indicating that autosomal recessive inheritance is likely.
blepharo-naso-facial malformation; camptodactyly; bilateral periventricular nodular heterotopia; autosomal recessive; choanal atresia; migration abnormalities
ICF syndrome is a rare autosomal recessive disorder that is characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In all, 60% of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements (mainly involving juxtacentromeric regions), and more than 700 genes are aberrantly expressed. This work shows that DNA replication is also altered in ICF cells: (i) heterochromatic genes replicate earlier in the S-phase; (ii) global replication fork speed is higher; and (iii) S-phase is shorter. These replication defects may result from chromatin changes that modify DNA accessibility to the replication machinery and/or from changes in the expression level of genes involved in DNA replication. This work highlights the interest of using ICF cells as a model to investigate how DNA methylation regulates DNA replication in humans.
ICF syndrome; DNA replication; DNA methylation
Aniridia is a rare congenital disorder in which there is a variable degree of hypoplasia or the absence of iris tissue associated with multiple other ocular changes, some present from birth and some arising progressively over time. Most cases are associated with dominantly inherited mutations or deletions of the PAX6 gene. This article will review the clinical manifestations, the molecular basis including genotype–phenotype correlations, diagnostic approaches and management of aniridia.
aniridia; PAX6; eye; iris; foveal hypoplasia; WAGR syndrome
Advances in sequencing technology allow assessing the impact of rare variation on common disorders. For this purpose, methods combine rare variants across a gene and compare an aggregate statistic between cases and controls. However, sequencing many individuals is costly. Hence, it is necessary to identify case samples that are most likely to result in powerful tests under realistic model assumptions. Power can be increased by selecting cases that are highly likely to carry risk variants. As rare variants that contribute to the heritability of a disease co-segregate among affected family members, selecting cases that have affected family members may increase the power of rare variant tests considerably. Here I compare sequencing random cases to cases ascertained to have affected family members. I quantify the power of the different approaches and provide criteria for sample selection under different models of inheritance. Under a model of multiplicative gene–gene interaction, a sample of random cases has to be 2–16-fold larger to achieve the same power as a sample of cases ascertained to have affected family members. However, in traits with high heritability this power gain can be reduced or even reversed under models of additive gene–gene interaction. Hence study designs should depend on the studied disease's heritability and on the available sample size. I also show that selecting cases that share both chromosomes identical by descent with an affected sibling at candidate regions can result in a further power gain.
rare variants; study design; family-based; burden test
Isolated cleft palate (CP) is common in humans and has complex genetic etiologies. Many
genes have been found to contribute to CP, but the full spectrum of genes remains unknown.
PCR-sequencing of the entire coding regions and the 3′ untranslated region (UTR) of
the platelet-derived growth factor receptor alpha (PDGFRa) and the microRNA
(miR), miR-140 identified seven novel single base-pair substitutions in the
PDGFRa in 9/102 patients with CP (8.8%), compared with 5/500
ethnic-matched unaffected controls (1%) (the two-tailed
P-value<0.0001). Of these seven, four were missense mutations in the coding
regions and three in the 3′UTR. Frequencies of four changes (three in coding, one in
3′UTR) were statistically different from those of controls
(P-value<0.05). The c.*34G>A was identified in 1/102 cases and
0/500 controls. This position is conserved in primates and located 10 bp away
from a predicted binding site for the miR-140. Luciferase assay revealed that, in
the presence of miR-140, the c.*34G>A significantly repressed luciferase
activity compared with that of the wild type, suggesting functional significance of this
variant. This is the first study providing evidence supporting a role of PDGFRa
in human CP.
PDGFRa; 3′UTR; microRNA; human cleft palate
Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary
movements of the eyeballs that most commonly presents between 2 and 6 months of life. To
date, 44 different FRMD7 gene mutations have been found to be etiological factors
for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene
mutations in a large eleven-generation Indian pedigree with 71 members who are affected by
NYS. Mutation analysis of the entire coding region and splice junctions of the
FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution
of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was
detected in hemizygous males, and in homozygous and heterozygous states in affected female
members of the family. This mutation was not detected in unaffected members of the family
or in 100 unrelated control subjects. This mutation was found to be at a highly conserved
residue within the FERM-adjacent domain in affected members of the family. Structure
prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R)
revealed that this change in amino acid led to a change in secondary structure predicted
to be an energetically unstable protein. The present study represents the first
confirmation of FRMD7 gene mutations in a multigenerational Indian family and
expands the mutation spectrum for this locus.
nystagmus; FRMD7 gene; mutation analysis
We report on the effectiveness of a custom-designed oligonucleotide-based comparative
genomic hybridization microarray (array-CGH) to interrogate copy number across the entire
2.2-Mb genomic region of the DMD gene and its applicability in diagnosis. The
high-resolution array-CGH, we developed, successfully detected a series of 42 previously
characterized large rearrangements of various size, localization and type (simple or
complex deletions, duplications, triplications) and known intronic CNVs/Indels.
Moreover, the technique succeeded in identifying a small duplication of only 191 bp
in one patient previously negative for DMD mutation. Accurate intronic
breakpoints localization by the technique enabled subsequent junction fragments
identification by sequencing in 86% of cases (all deletion cases and 62.5%
of duplication cases). Sequence examination of the junctions supports a role of
microhomology-mediated processes in the occurrence of DMD large rearrangements.
In addition, the precise knowledge of the sequence context at the breakpoints and analysis
of the resulting consequences on maturation of pre-mRNA contribute to elucidating the
cause of discrepancies in phenotype/genotype correlations in some patients. Thereby,
the array-CGH proved to be a highly efficient and reliable diagnostic tool, and the new
data it provides will have many potential implications in both, clinics and research.
duchenne muscular dystrophy; gene; large rearrangements; comparative genomic hybridization microarray; diagnostic methods