Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Molecular spectrum of inherited FVII deficiency in North India revealed a recurrent variant with a founder effect.

INTRODUCTION: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases. AIM: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency. METHODS: Retro-prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C) <50 IU/dl were subjected to targeted resequencing. After in-silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms. RESULTS: Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from .3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.-30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice-site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians. CONCLUSION: This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation.

The Impact of Genetic Surfing on Neutral Genomic Diversity.

Range expansions have been common in the history of most species. Serial founder effects and subsequent population growth at expansion fronts typically lead to a loss of genomic diversity along the expansion axis. A frequent consequence is the phenomenon of "gene surfing," where variants located near the expanding front can reach high frequencies or even fix in newly colonized territories. Although gene surfing events have been characterized thoroughly for a specific locus, their effects on linked genomic regions and the overall patterns of genomic diversity have been little investigated. In this study, we simulated the evolution of whole genomes during several types of 1D and 2D range expansions differing by the extent of migration, founder events, and recombination rates. We focused on the characterization of local dips of diversity, or "troughs," taken as a proxy for surfing events. We find that, for a given recombination rate, once we consider the amount of diversity lost since the beginning of the expansion, it is possible to predict the initial evolution of trough density and their average width irrespective of the expansion condition. Furthermore, when recombination rates vary across the genome, we find that troughs are over-represented in regions of low recombination. Therefore, range expansions can leave local and global genomic signatures often interpreted as evidence of past selective events. Given the generality of our results, they could be used as a null model for species having gone through recent expansions, and thus be helpful to correctly interpret many evolutionary biology studies.

Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study.

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.

A Founder Mutation in the POMC 5'-UTR Causes Proopiomelanocortin Deficiency Through Splicing-Mediated Decrease of mRNA.

CONTEXT: The syndrome of adrenal insufficiency, obesity, and red hair is a rare autosomal recessive disorder. The majority of disease-causing variants associated with the syndrome are located in the coding region of the POMC gene. OBJECTIVE: This work describes 7 unrelated patients who shared a novel homozygous mutation in the 5'-untranslated region (UTR) of the POMC gene and functionally characterize this novel variant. METHODS: Whole-exome sequencing (WES) with autozygosity mapping, Sanger sequencing, model expression system studies, and RNA sequencing were used for identification of the disease-causing variant and its subsequent functional characterization. Seven unrelated patients of the Perm Tatar ethnic group presented with hypoglycemia and excessive weight gain, low plasma adrenocorticotropin, and cortisol. Five of 7 children had red hair; 6 of 7 patients also showed signs of bronchial obstruction. RESULTS: WES showed shared autozygosity regions overlapping the POMC gene. Sanger sequencing of the POMC 5'-UTR detected a homozygous variant chr2:25391366C > T (hg19) at the splice donor site of intron 1. As demonstrated by the model expression system, the variant led to a significant decrease in the POMC messenger RNA level. Analyses of the patients' haplotypes were suggestive of the founder effect. We estimate that the mutation must have occurred at least 4.27 generations ago (95% CI, 0.86-7.67). CONCLUSION: This report presents a new molecular mechanism of POMC deficiency and contributes to the information on phenotypic variability in patients with this disorder.

Reconstructing the history of founder events using genome-wide patterns of allele sharing across individuals.

Founder events play a critical role in shaping genetic diversity, fitness and disease risk in a population. Yet our understanding of the prevalence and distribution of founder events in humans and other species remains incomplete, as most existing methods require large sample sizes or phased genomes. Thus, we developed ASCEND that measures the correlation in allele sharing between pairs of individuals across the genome to infer the age and strength of founder events. We show that ASCEND can reliably estimate the parameters of founder events under a range of demographic scenarios. We then apply ASCEND to two species with contrasting evolutionary histories: ~460 worldwide human populations and ~40 modern dog breeds. In humans, we find that over half of the analyzed populations have evidence for recent founder events, associated with geographic isolation, modes of sustenance, or cultural practices such as endogamy. Notably, island populations have lower population sizes than continental groups and most hunter-gatherer, nomadic and indigenous groups have evidence of recent founder events. Many present-day groups--including Native Americans, Oceanians and South Asians--have experienced more extreme founder events than Ashkenazi Jews who have high rates of recessive diseases due their known history of founder events. Using ancient genomes, we show that the strength of founder events differs markedly across geographic regions and time--with three major founder events related to the peopling of Americas and a trend in decreasing strength of founder events in Europe following the Neolithic transition and steppe migrations. In dogs, we estimate extreme founder events in most breeds that occurred in the last 25 generations, concordant with the establishment of many dog breeds during the Victorian times. Our analysis highlights a widespread history of founder events in humans and dogs and elucidates some of the demographic and cultural practices related to these events.

BRCA1 and BRCA2 screening of nine Chilean founder mutations through allelic-discrimination and real-time PCR in breast/ovarian cancer patients.

BACKGROUND: In a previous work, we identified nine founder mutations present in close to 80% of BRCA1 and BRCA2 mutation carriers, and distributed across the country. The presence of founder mutations constitutes a valuable opportunity to develop new strategies for genetic screening. Genetic tests are primarily performed by NGS sequencing, which requires sophisticated and expensive equipment, and it takes 2-3 weeks for the results to be informed to the patient. In addition, genetic tests are not covered by insurance companies in Latin American countries. In this work, we present the standardization and technical validation of a real-time PCR based methodology for allelic discrimination in order to identify the nine Chilean founder mutations in BRCA1 and BRCA2 genes. METHODS AND RESULTS: We designed nine pairs of probes and nine pairs of primers to amplify synchronically nine regions of the BRCA1/BRCA2 genes by real-time PCR, in order to identify the nine founder mutations through allelic discrimination analyses. Technical validation was performed using 90 positive and 90 negative samples for each mutation. The methodology was tested in a second group of 60 patients. Our method correctly classified carriers and non-carriers of one of the nine Chilean founder mutations with a 100% specificity and 100% sensitivity, compared with Sanger sequencing performance. CONCLUSIONS: We develop an inexpensive, simple, and fast mutation detection method that could be implemented locally in Hospitals from the Private to Public health system. This methodology may be useful for the screening of BRCA1 and BRCA2 mutations in other populations.

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations.

Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell­derived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

Hereditary hemorrhagic telangiectasia: First demonstration of a founder effect in Italy; the ACVRL1 c.289_294del variant originated in the country of Bergamo 200 years ago.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF-ß/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in-frame deletion c.289_294del (p.H97_N98). METHODS: To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non-carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out. RESULTS: We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site. CONCLUSION: We have demonstrated, for the first time, a "founder effect" for a HHT pathogenic variant in Italy.

Novel and recurrent ASPM mutations of founder effect in Chinese population.

PURPOSE: Mutations in ASPM are the most common causes of primary microcephaly (MCPH), which is a rare brain developmental disorder with few studies in Chinese population so far. This study aimed to identify the common pathogenic variants of ASPM and estimated the incidence of MCPH5 in Guangxi population. METHODS: We ascertained six MCPH cases caused by ASPM mutations in Guangxi Zhuang Autonomous Region, Whole-exome sequencing (WES) was performed to uncover the causal variants. The haplotype analysis was used to estimate the age of the recurrent variation. RESULTS: Five different pathogenic variants were identified in this batch of MCPH5 cases, including two novel variants p.Ser842fs*9 and p.Lys1340Argfs*29. An rarely reported pathogenic variant, c.1789C>T/p.Arg597* was found to be a founder mutation in local population. We evaluated all ASPM variants detected among 2674 non-microcephalic individuals and estimated the MCPH5 incidence to be 5.03/1,000,000 in Guangxi population. CONCLUSIONS: We reported the first case series of Chinese MCPH cases with ASPM mutation and revealed a highly recurrent founder mutation in this local population. MCPH5 may be the major type of congenital microcephaly in Chinese population.

Predominant Founder Effect among Recurrent Pathogenic Variants for an X-Linked Disorder.

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.

An Amish founder population reveals rare-population genetic determinants of the human lipidome.

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants.

Chasing the origin of 23 recurrent BRCA1 mutations in Pakistani breast and ovarian cancer patients.

Knowledge of population specific BRCA1/2 founder mutations provides a valuable and cost-effective genetic testing strategy. Twenty-three recurrent BRCA1 mutations have been identified previously in 100 Pakistani breast and/or ovarian cancer families. These accounted for 72.5% of all BRCA1 mutations identified. In our study, we investigated whether these mutations (identified in ≥2 unrelated patients) have a common ancestral origin and estimated the ages of these mutations. Haplotype analyses were performed in 188 individuals (100 index patients, 88 relatives) from Pakistani breast/ovarian cancer families, all harboring one of the 23 recurrent BRCA1 mutations, and 90 healthy controls. Six microsatellite markers (D17S800, D17S1801, D17S855, D17S1322, D17S1323, and D17S951) were analyzed. Mutation ages were estimated using DMLE+2.3 software. An identical haplotype of different length was found in families harboring the same BRCA1 mutation and suggested founder effects for all 23 mutations. Sixteen founder mutations were ethnicity-specific: 15 occurred in families of Punjabi background and one in a family of Pathan background. The remaining seven mutations occurred in families with two ethnic backgrounds. All BRCA1 founder mutations were estimated to have arisen approximately 147 to 159 generations ago. Our findings suggest founder effects for all 23 recurrent BRCA1 mutations. This knowledge allows the design and development of a cost effective local genetic testing strategy in Pakistan.

Novel alleles gained during the Beringian isolation period.

During the Last Glacial Maximum, a small band of Siberians entered the Beringian corridor, where they persisted, isolated from gene flow, for several thousand years before expansion into the Americas. The ecological features of the Beringian environment, coupled with an extended period of isolation at small population size, would have provided evolutionary opportunity for novel genetic variation to arise as both rare standing variants and new mutations were driven to high frequency through both neutral and directed processes. Here we perform a full genome investigation of Native American populations in the Thousand Genomes Project Phase 3 to identify unique high frequency alleles that can be dated to an origin in Beringia. Our analyses demonstrate that descendant populations of Native Americans harbor 20,424 such variants, which is on a scale comparable only to Africa and the Out of Africa bottleneck. This is consistent with simulations of a serial founder effects model. Tests for selection reveal that some of these Beringian variants were likely driven to high frequency by adaptive processes, and bioinformatic analyses suggest possible phenotypic pathways that were under selection during the Beringian Isolation period. Specifically, pathways related to cardiac processes and melanocyte function appear to be enriched for selected Beringian variants.

Spectrum of NPHS1 and NPHS2 variants in egyptian children with focal segmental glomerular sclerosis: identification of six novel variants and founder effect.

The aim of this study is to screen for variants in NPHS1 and NPHS2, in a cohort of Egyptian children with steroid-resistant nephrotic syndrome (SRNS)/focal segmental glomerulosclerosis (FSGS) and compare the prevalence of such variants among other ethnic groups. The study included 25 patients: 21 children diagnosed clinically as steroid-resistant nephrotic syndrome and confirmed as FSGS by renal biopsy and four patients diagnosed as congenital nephrotic syndrome with FSGS. Mutational analysis revealed nine NPHS2 and NPHS1 variants in 13/25 patients with a pathogenic variant detection rate of 52%. NPHS2 variants were found in 8 patients (32%) while five patients from four unrelated families (20%) harbored variants in NPHS1 gene. Six variants were not described before including a likely founder NPHS2 variant in our population, c.596dupA (p.Asn199LysfsTer14). In conclusion, we reported the largest series of patients with SRNS/FSGS from Egypt and identified many novel NPHS1 and NPHS2 variants expanding their mutational spectrum. Further studies on a larger number of patients could provide new insights into the pathogenic mechanisms of SRNS/FSGS which might help in patient's management and prognosis.

Common founder BRCA2 pathogenic variants and breast cancer characteristics in Ethiopian Jews.

PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Novel and founder variants of SERPINA12 in Chinese patients with autosomal recessive palmoplantar keratoderma.

1. We extend the spectrum of SERPINA12 variants in palmoplantar keratodermas. 2. The recurrent variant c.970_971del, mainly prevalent in the East Asia population, was proved to be a founder variant. 3. Considerable SERPINA12-related palmoplantar keratoderma patients could be identified from autosomal recessive, non-mutilating, diffused palmoplantar keratoderma patients. 4. Other serpin family members or their co-effect may participate in the etiologies of underexplored hereditary palmoplantar keratodermas.

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG.

Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.

Mucolipidosis Type IV in Omani Families with a Novel MCOLN1 Mutation: Search for Evidence of Founder Effect.

Mucolipidosis Type IV (MLIV) is caused by a deficiency of the mucolipin cation channel encoded by Mucolipin TRP Cation Channel 1 gene (MCOLN1). It is a slowly progressive neurodevelopmental and neurodegenerative disorder causing severe psychomotor developmental delay and progressive visual impairment, which is often misdiagnosed as cerebral palsy. We describe six patients with MLIV from two Omani families with a novel c.237+5G>A mutation in the MCOLN1 gene predicted to affect mRNA splicing. Mutation screening with a high-resolution melting (HRM) assay in a large population sample did not detect this mutation in control subjects. This report highlights the importance of considering MLIV in the differential diagnosis of patients in a pediatric age group with cerebral palsy-like presentation. Although the same rare mutation was seen in two apparently unrelated families, this was not seen in the sample screened from the general population. The HRM assay provides a cost-effective assay for population screening for the c.237+5G>A mutation.