Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

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Hall-effect and sheet-resistivity measurements have been made on silicon samples implanted with Sb, Ga, and As ions at energies between 20 and 75 keV. These measurements determine the weighted average of the number Ns of carriers/cm2 and the carrier mobility in the implanted layer. A combination of Hall measurements and layer-removal techniques was used in some cases to obtain a more accurate value of the number of carriers/cm2 and the depth dependence of the carrier concentration and mobility.For Sb implantations both temperature and dose affect the anneal characteristics. Silicon samples implanted with Sb at room temperature exhibited n-type behavior following anneal at 300 °C, with little increase in Ns up to about 550 °C anneal temperatures. A 600 °C 10-minute anneal produced an order-of-magnitude increase in Ns. This change is associated with reordering of the amorphous layer created during room-temperature implantations. This amorphous layer is not produced in implantations made at temperatures above 450 °C. In low-dose (<1014/cm2) Sb implantations at 500 °C, Ns increased by a factor of 2 to 3 during anneal to 800 °C. In high-dose (>5 × 1014/cm2) Sb implantations, the carrier concentration exceeded the limit set by thermal equilibrium solubility of Sb in silicon. Under these conditions, annealing caused a decrease in Ns toward the value associated with the solubility.Such supersaturation effects were not observed in Ga and As implantations at 500 °C. Annealing to temperatures of 800–900 °C produced a one-to-two order-of-magnitude increase in the number of carriers/cm2. In Ga implantations annealed to 800–900 °C, the number of carriers/cm2 increased approximately linearly with increasing dose and then leveled off at a value near that expected from thermal solubility.The Rutherford-scattering data in the preceding paper indicates that the difference in implantation behavior between various ion species is due to differences in the relative number of ions on substitutional sites.

The anneal behavior of layers implanted with dopants from column III (B, Al, Ga, and Tl) and column V (As, Sb, and Bi) in silicon substrates has been investigated. The ranges of implant conditions were energy 20–50 keV, dose 1013–1015/cm2, and substrate temperature 23°–500°C. Hall-effect and sheet resistivity measurements were used to determine the effective number of carriers/cm2 (Ns)eff and the effective mobility μeff. Analysis of nonuniform distributions of carrier densities and mobilities on these measurements shows that the values of (Ns)eff and μeff can be misleading unless the effect of the depth distributions is allowed for. These distributions have been determined in some cases by the use of layer removal techniques combined with Hall-effect and sheet resistivity measurements. We find in well-annealed implanted samples that the dependence of the mobility on carrier density follows that determined for bulk silicon. In many cases deviation from this relation can be accounted for on the basis of compensation. In the case of aluminum we suggest that this compensation may be accounted for by the presence of interstitial aluminum atoms acting as donors. We have found that interstitial thallium can behave as a donor. The anneal behavior of the implanted layer is influenced by ion species, dose, and substrate temperature. The carrier concentration measured in implantations of column III elements did not exceed the limits of thermal equilibrium solubility as is found for column V elements. In the former case, enhanced diffusion effects are observed. From the known substitutional behavior of column V elements, it is suggested that the anneal behavior in the 600°–800°C range is due to the dissociation of radiation damage complexes.

A new acceptor level located 0.111±0.002 eV from the valence band with a peak photoionization cross section of (1.4±0.6) ×10−16 cm2 has been observed in indium-doped silicon. Its presence is revealed both by the low-temperature slope of Hall measurements versus temperature and by the spectral response of the photoconductivity. The concentration of this 0.111-eV level is strongly correlated with the concentration of indium, suggesting that an In complex is responsible for this center.