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Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.

The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioral. The effectiveness of various non-pharmaceutical interventions can largely be attributed to changes in human behavior, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to compare the infectiousness of distinct groups of persons directly. We find that people diagnosed outside of quarantine are 89% more infectious than those diagnosed while in quarantine, and infectiousness decreases as a function of the time spent in quarantine. Furthermore, we find that people of working age, 16-66 years old, are 47% more infectious than those outside that age range. Lastly, the transmission tree enables us to model the effect that given population prevalence of vaccination would have had on the third wave had they been administered before that time using several different strategies. We find that vaccinating in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age.

BACKGROUNDLimited data exist on how SARS-CoV-2 enters and spreads in the general population.METHODSWe used two strategies for SARS-CoV-2 testing: targeted testing of high-risk individuals (n=4,551) and a population screening (n=5,502). We sequenced SARS-CoV-2 from 340 individuals.RESULTSOn March 22 2020, 528 had tested positive for SARS-CoV-2 in the targeted testing (11.6%) and 50 in the population screening (0.9%); approximately 0.2% of the Icelandic population. Large fractions of positives had travelled outside Iceland (38.4% and 34.0%). Fewer under 10 years old were positive than those older: 2.8% vs. 12.3% for targeted testing (P=1.6e-9) and 0.0% vs. 1.0% for population screening (P=0.031). Fewer females were positive in the targeted testing than males (9.5% vs. 14.6%, P=6.8e-9). SARS-CoV-2 came from eight clades, seven A clades and one B clade. The clade composition differed between the testing groups and changed with time. In the early targeted testing, 65.0% of clades were A2a1 and A2a2 derived from Italian and Austrian skiing areas, but in the later targeted testing went down to 30.6% and were overtaken by A1a and A2a, the most common clades in the population screening.CONCLUSIONSARS-CoV-2 has spread widely in Iceland outside of the high-risk groups. Several strains cause these infections and their relative contribution changed rapidly. Children and females are less vulnerable than adults and males. To contain the pandemic we must increase the scope of the testing.

A third survey of multiple sclerosis (MS) in Iceland has been performed covering the decade 1956–1965 and the patients have been followed-up to 1973. The same diagnostic criteria have been used as in the second survey (1946–1955). During the period 37 new patients were encountered and, of these, 34 were classified as definitely or probably suffering from MS. The whole material, i.e. including MS-patients alive or dead at some time during 1946–1965, now amounts to 129 definite and probable cases of which 50 are males and 79 are females, and 13 possible cases of which 7 are males and 6 are females. The possible cases are not included in the statistical figures in this abstract. The mean age at onset was higher in this survey than in the second survey, i.e. 32 years as compared to 27 before. In 1960 the prevalence rate was 42.8 100,000 for males, 62.1 for females and 52.4 for both sexes, and in 1965 the figures were 44.0, 60.7 and 52.3 respectively. The age-specific prevalence rate was highest in the age groups 30–39 and 40–49, figures similar to those obtained in the second survey. The incidence rate during the survey period 1956–1965 was 1.9 100,000 per annum. In the previous decade it was somewhat higher at 3.1 100,000 per annum. There were 9 families containing more than 1 case and the familial incidence was 7.0%. There was some evidence of accumulation of cases in Eastern Iceland and of a local accumulation in Southern Iceland.

Since 1974 we have attempted to ascertain all cases of MS beginning 1900–1975 in Iceland. As of October 1979 they numbered 168; all but 5 met all diagnostic criteria of the Schumacher Committee. Virtually all cases had been examined by at least one of the authors. Cases were few and sporadic from 1900 to 1922, then increased to a plateau for 1923–44, then again increased in 1945 with an irregular plateau thereafter. Average annual incidence rate for 1945–1954 was 3.2 per 100,000 population, significantly higher than the 1.6 for 1923–1944 or the 1.9 for 1955–1974. Age at onset was significantly decreased for cases with onset 1945–1949 and then sharply increased for those with 1950–1954 onsets. The occurrence of MS in 1945–1954 meets the criteria for a point-source epidemic, whose tail thereafter merged into what may be “baseline” for Iceland. This postwar epidemic is then similar to that recently described for the Faroe Islands, a land that shares its history, culture, and peoples with Iceland.