Runs of homozygosity in sub-Saharan African populations provide insights into complex demographic histories In the Original article published, the figure number 5: Genomic distribution of ROH is incorrectly published. The correct figure is given below.

COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans Abstract Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

Runs of homozygosity in sub-Saharan African populations provide insights into complex demographic histories Abstract The study of runs of homozygosity (ROH) can shed light on population demographic history and cultural practices. We present a fine-scale ROH analysis of 1679 individuals from 28 sub-Saharan African (SSA) populations along with 1384 individuals from 17 worldwide populations. Using high-density SNP coverage, we could accurately identify ROH > 300 kb using PLINK software. The genomic distribution of ROH was analysed through the identification of ROH islands and regions of heterozygosity (RHZ). The analyses showed a heterogeneous distribution of autozygosity across SSA, revealing complex demographic histories. They highlight differences between African groups and can differentiate the impact of consanguineous practices (e.g. among the Somali) from endogamy (e.g. among several Khoe and San groups). Homozygosity cold and hotspots were shown to harbour multiple protein coding genes. Studying ROH therefore not only sheds light on population history, but can also be used to study genetic variation related to adaptation and potentially to the health of extant populations.

GPT2 mutations in autosomal recessive developmental disability: extending the clinical phenotype and population prevalence estimates Abstract The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.

Autosomal recessive diseases among the Israeli Arabs Abstract The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze. Data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database. Among the Israeli Arabs in December 31 2018, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria or congenital adrenal hyperplasia as well as data on 632 autosomal recessive diseases among Muslim Israeli Arabs, 52 among the Christian Arabs and 79 among Druze. A single variant was characterized in 590 out of the 771 genes causing disorders in which the molecular basis was known. Many of the variants reported among Arabs in Israel are novels, most being found in one community only. Some variants are ancient and for instance, consistent with the migration history, several variants are found in the Bedouins from the Negev as well as from the Arab peninsula. In the 181 other disorders more than one variant was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases the reason may be a selective advantage to the heterozygotes.

The rare 13q33–q34 microdeletions: eight new patients and review of the literature Abstract The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33–q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1–q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1–q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10–30% of the cases. None of the 13q33–q34 deletions were inherited from a reported healthy parent. 13q33–q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.

Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish Abstract Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants across 175 samples for association and linkage analyses. After correcting for multiple testing (n = 37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p = 1.50 × 10−11), rs151214675 (RTEL1, p = 3.18 × 10−8), rs140250387 (DLGAP1, p = 4.49 × 10−7), and rs115333865 (CGRRF1, p = 1.05 × 10−6). These variants have not been previously associated with AMD and are not in linkage disequilibrium with the 52 known AMD-associated variants reported by the International AMD Genomics Consortium based on physical distance. Genome-wide significant linkage peaks were observed on chromosomes 8q21.11–q21.13 (maximum recessive HLOD = 4.03) and 18q21.2–21.32 (maximum dominant HLOD = 3.87; maximum recessive HLOD = 4.27). These loci do not overlap with loci previously linked to AMD. Through gene ontology enrichment analysis with ClueGO in Cytoscape, we determined that several genes in the 1-HLOD support interval of the chromosome 8 locus are involved in fatty acid binding and triglyceride catabolic processes, and the 1-HLOD support interval of the linkage region on chromosome 18 is enriched in genes that participate in serine-type endopeptidase inhibitor activity and the positive regulation of epithelial to mesenchymal transition. These results nominate novel variants and loci for AMD that require further investigation.

Novel truncation mutations in MYRF cause autosomal dominant high hyperopia mapped to 11p12–q13.3 Abstract High hyperopia is a common and severe form of refractive error. Genetic factors play important roles in the development of high hyperopia but the exact gene responsible for this condition is mostly unknown. We identified a large Chinese family with autosomal dominant high hyperopia. A genome-wide linkage scan mapped the high hyperopia to chromosome 11p12–q13.3, with maximum log of the odds scores of 4.68 at theta = 0 for D11S987. Parallel whole-exome sequencing detected a novel c.3377delG (p.Gly1126Valfs*31) heterozygous mutation in the MYRF gene within the linkage interval. Whole-exome sequencing in other 121 probands with high hyperopia identified additional novel mutations in MYRF within two other families: a de novo c.3274_3275delAG (p.Leu1093Profs*22) heterozygous mutation and a c.3194+2T>C heterozygous mutation. All three mutations are located in the C-terminal region of MYRF and are predicted to result in truncation of that portion. Two patients from two of the three families developed angle-closure glaucoma. These three mutations were present in neither the ExAC database nor our in-house whole-exome sequencing data from 3280 individuals. No other truncation mutations in MYRF were detected in the 3280 individuals. Knockdown of myrf resulted in small eye size in zebrafish. These evidence all support that truncation mutations in the C-terminal region of MYRF are responsible for autosomal dominant high hyperopia in these families. Our results may provide useful clues for further understanding the functional role of the C-terminal region of this critical myelin regulatory factor, as well as the molecular pathogenesis of high hyperopia and its associated angle-closure glaucoma.

Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues Abstract Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10−8 across regulatory categories. We then obtained annotations for DNaseI hypersensitive sites (DHS), typical enhancers, and super enhancers across multiple tissue types, to assess if significant GWAS signals were selectively enriched in annotations found in disease-related tissue. Finally, we quantified the enrichment of breast and prostate cancer SNP heritability in regulatory regions, and compared the enrichment pattern of SNP heritability with GWAS signals. DHS, typical enhancers, and super enhancers identified in the breast cancer cell line MCF-7 were observed with the highest enrichment of genome-wide significant variants for breast cancer. For prostate cancer, GWAS signals were mostly enriched in DHS and typical enhancers identified in the prostate cancer cell line LNCaP. With progressively stringent GWAS p value thresholds, an increasing trend of enrichment was observed for both diseases in DHS, typical enhancers, and super enhancers located in disease-related tissue. Results from heritability enrichment analysis supported the selective enrichment pattern of functional genomic regions in disease-related cell lines for both breast and prostate cancer. Our results suggest the importance of studying functional annotations identified in disease-related tissues when characterizing GWAS results, and further demonstrate the role of germline DNA regulatory elements from disease-related tissue in breast and prostate carcinogenesis.

A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss Abstract While the importance of tight junctions in hearing is well established, the role of Claudin- 9 (CLDN9), a tight junction protein, in human hearing and deafness has not been explored. Through whole-genome sequencing, we identified a one base pair deletion (c.86delT) in CLDN9 in a consanguineous family from Turkey with autosomal recessive nonsyndromic hearing loss. Three affected members of the family had sensorineural hearing loss (SNHL) ranging from moderate to profound in severity. The variant is predicted to cause a frameshift and produce a truncated protein (p.Leu29ArgfsTer4) in this single-exon gene. It is absent in public databases as well as in over 1000 Turkish individuals, and co-segregates with SNHL in the family. Our in vitro studies demonstrate that the mutant protein does not localize to cell membrane as demonstrated for the wild-type protein. Mice-lacking Cldn9 have been shown to develop SNHL. We conclude that CLDN9 is essential for proper audition in humans and its disruption leads to SNHL in humans.