Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype

The chromosome 17q21.31 deletion syndrome is a genomic disorder characterized by highly distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior. Here, we show that de novo loss-of-function mutations in KANSL1 (also called KIAA1267) cause a full del(17q21.31) phenotype in two unrelated individuals that lack deletion at 17q21.31. These findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1.     

Structural diversity and African origin of the 17q21.31 inversion polymorphism

The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2') lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps.     

Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.     

A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.     

Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability

Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs). The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.     

A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is most often caused by hemizygous deletion of a 1.5-Mb interval encompassing at least 17 genes at 7q11.23 (refs. 1,2). As with many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region. Here, we report the use of interphase fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS region. We have observed that the inversion is hemizygous in 3 of 11 (27%) atypical affected individuals who show a subset of the WBS phenotypic spectrum but do not carry the typical WBS microdeletion. Two of these individuals also have a parent who carries the inversion. In addition, in 4 of 12 (33%) families with a proband carrying the WBS deletion, we observed the inversion exclusively in the parent transmitting the disease-related chromosome. These results suggest the presence of a newly identified genomic variant within the population that may be associated with the disease. It may result in predisposition to primarily WBS-causing microdeletions, but may also cause translocations and inversions.     

Common variants at 6q22 and 17q21 are associated with intracranial volume

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.     

A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone

Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.     

Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A.

Charcot-Marie-Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein-22 (pmp-22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP-22 gene to the duplicated region. These observations further implicate PMP-22 as a candidate gene for CMT1A, and suggest that over-expression of this gene may be one mechanism that produces the CMT1A phenotype.     

The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.     

Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome

Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.     

A common variant associated with prostate cancer in European and African populations

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.     

A common coding variant in CASP8 is associated with breast cancer risk

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.     

Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10(-10)) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.     

A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is a pediatric spinal deformity affecting 2-3% of school-age children worldwide(1). Genetic factors have been implicated in its etiology(2). Through a genome-wide association study (GWAS) and replication study involving a total of 1,376 Japanese females with adolescent idiopathic scoliosis and 11,297 female controls, we identified a locus at chromosome 10q24.31 associated with adolescent idiopathic scoliosis susceptibility. The most significant SNP (rs11190870; combined P = 1.24 × 10(-19); odds ratio (OR) = 1.56) is located near LBX1 (encoding ladybird homeobox 1). The identification of this susceptibility locus provides new insights into the pathogenesis of adolescent idiopathic scoliosis.