Am J Hum Genet

Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the γ-subunit gene (CHRNG) of the AChR. Our functional studies show that γ-subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney–cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two α, one β, and one δ subunit are always present. By switching γ to ϵ subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the γ subunit were thought to be lethal, as they are in γ-knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because γ expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway

Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits

Despite the recent rapid growth in genome-wide data, much of human variation remains entirely unexplained. A significant challenge in the pursuit of the genetic basis for variation in common human traits is the efficient, coordinated collection of genotype and phenotype data. We have developed a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the Web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design. Here we report initial results from a participant-driven study of 22 traits. Replications of associations (in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, TYR, TYRP1, ASIP, and MC1R) for hair color, eye color, and freckling validate the Web-based, self-reporting paradigm. The identification of novel associations for hair morphology (rs17646946, near TCHH; rs7349332, near WNT10A; and rs1556547, near OFCC1), freckling (rs2153271, in BNC2), the ability to smell the methanethiol produced after eating asparagus (rs4481887, near OR2M7), and photic sneeze reflex (rs10427255, near ZEB2, and rs11856995, near NR2F2) illustrates the power of the approach

Genetic prediction of male pattern baldness

Male pattern baldness can have substantial psychosocial effects, and it has been phenotypically linked to adverse health outcomes such as prostate cancer and cardiovascular disease. We explored the genetic architecture of the trait using data from over 52,000 male participants of UK Biobank, aged 40-69 years. We identified over 250 independent genetic loci associated with severe hair loss (P<5x10-8). By splitting the cohort into a discovery sample of 40,000 and target sample of 12,000, we developed a prediction algorithm based entirely on common genetic variants that discriminated (AUC = 0.78, sensitivity = 0.74, specificity = 0.69, PPV = 59%, NPV = 82%) those with no hair loss from those with severe hair loss. The results of this study might help identify those at greatest risk of hair loss, and also potential genetic targets for intervention

Novel missense mutation in the <it>RSPO4</it> gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I)

<p>Abstract</p> <p>Background</p> <p>Anonychia/hyponychia congenita is a rare autosomal recessive developmental disorder characterized by the absence (anonychia) or hypoplasia (hyponuchia) of finger- and/or toenails frequently caused by mutations in the <it>R-spondin 4</it> (<it>RSPO4</it>) gene.</p> <p>Methods</p> <p>Three hypo/anonychia consanguineous Pakistani families were ascertained and genotyped using microsatellite markers spanning the <it>RSPO4</it> locus on chromosome 20p13<b>.</b> Mutation screening of the <it>RSPO4</it> gene was carried out by direct sequencing of the entire coding region and all intron-exon boundaries.</p> <p>Results</p> <p>Mutations in the <it>RSPO4</it> gene were identified in all families including a novel missense mutation c.178C>T (p.R60W) and two recurrent variants c.353G>A (p.C118Y) and c.3G>A (p.M1I). The c.3G>A variant was identified in unaffected family members and a control sample in a homozygous state.</p> <p>Conclusions</p> <p>This study raises to 17 the number of known <it>RSPO4</it> mutations and further expands the molecular repertoire causing hypo/anonychia. The c.353G>A emerges as a recurrent change with a possible founder effect in the Pakistani population. Our findings suggest that c.3G>A is not sufficient to cause the disorder and could be considered a polymorphism.</p

Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans

Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining ∼6% of variance (p = 1.5 × 10−31). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations