Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French Canadian founder population

Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP- N- acetylglucosamine:lysosomal enzyme N- acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay–Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.     

Autosomal recessive disorders in Saguenay-Lac-Saint-Jean (Quebec, Canada): a study of inbreeding

Saguenay Lac-Saint-Jean (SLSJ) is a geographically isolated region of northeastern Quebec in which several autosomal recessive disorders have a high incidence. We calculated the inbreeding coefficients of 567 probands and compared them to 1701 matched control individuals. The mean inbreeding coefficient of the group containing all 567 probands was 2·73 times higher than that of the controls (0·001772 versus 0·00065). Thirteen percent (75/567) of the probands were inbred, but only 5% were born to matings between spouses related as second-degree cousins or closer. No marriage between uncle and niece and only two marriages between first-degree cousins were identified in the disorder group. These results strongly suggest that the high incidence of the autosomal recessive disorders in SLSJ is the result of a founder effect.     

Population genetics of vitamin D-dependent rickets in northeastern Quebec

Vitamin D-dependent rickets (VDD1) is an autosomal recessive disorder that was recognized in Saguenay-Lac-St-Jean (SLSJ) in 1970. The great majority of the VDDl cases reportedin the French Canadian population of Quebec originated from SLSJ, Charlevoix, and the Haute CGte Nord, all regions located in northeastern Quebec. The prevalence a t birth in SLSJ was estimated a t 112916 live borns, and the carrier rate was estimated a t 1/27 inhabitants in the SLSJ region. The mean coefficient of inbreeding was not elevated in the VDDlgroup of SLSJ compared with three matched control groups. The mean coefficient of kinshipwas 2.5 times higher in the VDDl group than in the control groups. In the SLSJ region, the places of origin of the VDDl children and their children did not show a clustered non-uniform distribution. Endogamy was not found to be higher in the VDDl group than in controlgroups. The genealogical reconstruction showed all the obligate carriers of the VDDl gene, but one, to be related to a small set of founders who settled in New France in the 17thcentury. All these results, as well as a strong linkage disequilibrium between RFLPs located on the long arm of chromosome 12 and the VDDl locus, support the hypothesis of a founder effect for VDDl. They also suggest that a unique mutation accounts for most, if not all, of the cases known in northeastern Quebec.     

Genetic epidemiology of cystic fibrosis in Saguenay-Lac-St-Jean (Quebec, Canada)

Cystic fibrosis (CF) is an autosomal recessive disorder with a prevalence at birth estimated at 1/2000-1/2500 livebirths in Caucasian populations. Some 127 CF individuals are known in Saguenay-Lac-St-Jean (SLSJ), a geographically isolated region of Quebec. The prevalence at birth was estimated at 1/902 live borns, and the carrier rate was estimated at 1/15 inhabitants in the SLSJ region. The mean inbreeding coefficient was only slightly elevated in the CF group compared with three control groups, and was due to remote consanguinity. The mean kinship coefficient was 2.4 times higher in the CF group than in the control groups. In SLSJ region, the places of origin of the CF individuals and their parents did not show a clustered nonuniform distribution. Endogamy was not higher in the CF group than in control groups.     

Genetic diseases in the Tunisian population

Tunisia is one of the North African countries, geographically situated in a central position at the crossroad between Africa and Europe. The demographic features of the Tunisian population include among others high rates of consanguinity. We report, here on the spectrum of genetic diseases in Tunisia. The review of the literature, including other available information (gray literature) showed that there are at least 346 genetic disorders for which cases have been identified in the Tunisian population. Among these, 62.9% are autosomal recessive, 23% autosomal dominant, 5.4% X-linked, and the remaining are of Y-linked, mitochondrial, and unknown mode of transmission. Fifty percent of the reported conditions in this study are caused by at least one mutation. For autosomal recessive diseases, most of the mutations were identified at homozygous state among the affected individuals. Part of the mutations was the result of a founder effect; these are the consequences of the high rate of consanguinity. The congenital malformations, diseases of the nervous system and metabolic disorders are the major groups of genetic diseases affecting the Tunisian population. The large spectrum of diseases and their relatively high frequency could be explained by the high degree of inbreeding and the presence of multiple mutations, either allelic or in different genes. This is due to the richness of the genetic background of the studied population. A multidisciplinary approach is essential to develop adequate preventive programmes adapted to the social, cultural, and economic context.     

High carriers frequency of an apparently ancient founder mutation p.Tyr322X in the ERCC8 gene responsible for Cockayne syndrome among Christian Arabs in Northern Israel

Most autosomal recessive diseases are rare in the general population, but in genetically isolated communities specific condition might be frequent, mainly due to founder effect. Recognition of common inherited disorders in defined populations may be effective in improving public health care. Cockayne syndrome (CS) is a rare autosomal recessive disorder common in Christian Arabs due to a p.Tyr322X mutation. Genetic screening of the p.Tyr322X mutation of the ERCC8 gene in this population documented a carrier frequency of 6.79% (95% confidence interval: 3.84-9.74%). The haplotype analysis data, as well as the high carriers frequency of CS, suggested that the Israeli Arab Christian CS mutation (p.Tyr322X) is an ancient founder mutation that may have originated in the Christian Lebanese community. As a result of this pilot study the Christian CS mutation was included in the genetic screening program offered to the Israeli Arab Christian community.     

A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population

ABSTRACT: BACKGROUND: Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved. METHODS: We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990--2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation. RESULTS: A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein. CONCLUSION: We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.     

Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease‐causing variants

The Ashkenazi Jewish (AJ) population has an increased risk for a variety of recessive diseases due to historical founder effects and genetic drift. For some, the disease‐causing founder mutations have been identified and well‐characterized, but for others, further study is necessary. The purpose of this study is to assess the carrier frequencies of 85 pathogenic variants causative of 29 recessive conditions in the AJ population. Up to 3000 AJ individuals were genotyped by Luminex MagPlex^®‐TAG^? bead array or Agena Bioscience^? MassARRAY assays. We identified seven conditions with carrier frequencies higher than 1 in 100, nine between 1 in 100 and 1 in 200, and four between 1 in 200 and 1 in 500. Variants in nine conditions had a detected carrier rate of less than 1 in 500 or were not identified in approximately 2000 AJ individuals. We assessed the combined AJ carrier frequency for 18 relatively prevalent diseases to be 1 in 6, and the risk of AJ individuals to be a carrier couple for one of these 18 diseases as 1 in 441. We note additional recessive genetic conditions should be considered for AJ carrier screening panels.     

Autosomal recessive diseases among Palestinian Arabs.

As a consequence of the high consanguinity rate among the Palestinian Arabs, many recessive disorders are present with a relatively high frequency. In a survey of 2000 different Palestinian Arab families who visited our genetic clinic, in 601 an autosomal recessive disease was diagnosed or strongly suspected. The distribution of these disorders was not uniform and some disorders, such as Krabbe disease, were found at high frequency in only a small part of the population. For some other disorders, a high prevalence was also reported among Palestinian Arabs living in other regions, for example, beta thalassaemia, Bardet-Biedl syndrome, Meckel syndrome, autosomal recessive congenital hydrocephalus, and recessive osteopetrosis. In addition, as another consequence of the high consanguinity rate, two different autosomal recessive diseases were diagnosed within the same sibship in 17 of the Palestinian Arab families.     

Molecular basis of autosomal recessive diseases among the Palestinian Arabs

In the review of the literature, 71 different autosomal recessive diseases have been delineated that are relatively frequent among Palestinian Arabs. Among those, in 40 the mutation(s) responsible for the diseases are known. Fourteen of these disorders were caused by a single mutation, while the other 26 were due to multiple mutations. Most of the mutations were found in homozygosity among the affected patients. It is probable that the high frequency of most of the genetic diseases among the Palestinian Arabs is due to a founder effect as the result of the high consanguinity rates in this population. However, in some cases the high frequency was demonstrated to be secondary to the presence of multiple mutations, either allelic or in different genes in a small geographic region. This phenomenon remains unexplained but may be secondary to a selective advantage to the carriers, either specific to the region or to the population.     

Clinical Applications and Implications of Common and Founder Mutations in Indian Subpopulations

South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current‐day Indian population. With the evolving socio‐religious and economic activities of the subsects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal‐recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first‐hand affordable diagnostic and carrier screening tool. Here, we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective.     

Population history and its impact on medical genetics in Quebec

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French-Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle-France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix-Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French-Canadian-type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).     

Niemann Pick Disease type A in Israeli Arabs: 677delT, a common novel single mutation. Mutations in brief no. 161. Online

A novel single base pair deletion in the acid sphingomyelinase (ASM) gene (677delT in the cDNA) was identified in 12 Israeli Arab families with Niemann-Pick disease (NPD) type A. This deletion creates a premature stop codon which explains the complete deficiency of ASM activity in these patients and the severe clinical manifestation. A single mutation in 12 families living in a relatively small geographical region suggests a founder effect and explains the high frequency of this disease in this population. This is in contrast to multiple mutations found in two other lysosomal storage disorders prevalent in this population, namely, Hurler disease (MPSI) and metachromatic leukodystrophy. Mutations analysis is therefore an important tool in characterizing the grounds for the high frequency of inherited diseases as well as a basis for prevention programs for prevalent diseases through carrier identification and the ascertainment of high risk families.     

Identification of C12orf4 as a gene for autosomal recessive intellectual disability

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034‐429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co‐segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub‐isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.     

Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden

BackgroundMost autosomal recessive diseases are rare, but they collectively account for a substantial proportion of disease burden, especially in consanguineous populations. Estimation of this disease burden, however, is hampered by many factors, including lack of countrywide registries. Establishing carrier frequency can be a practical surrogate to estimate disease burden, although the requirement of a large representative cohort may be challenging.PurposeWe propose that the application of clinical genomics in the diagnostic setting offers a unique opportunity to estimate carrier frequency in the population as a secondary benefit.MethodsWe used a data set of ~7,100 patients who underwent genomic testing for various Mendelian disorders to estimate the carrier frequency.ResultsWe were able to calculate the frequency of 259 confirmed founder recessive mutations. We found the corresponding disease burden to be, at minimum, ~7 per 1,000 children born to first-cousin parents, with disorders related to intellectual disability and vision impairment being the most common.ConclusionOur approach can be utilized to inform the design of new policies for the prevention of genetic disorders and highlights an important secondary benefit of clinical genomics.Genet Med 18 12, 1244–1249.     

Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases

The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease‐causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ‐descended individuals, screening for 16 disorders resulted in ～1 in 3.3 being a carrier for one disease and ～1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ～15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease‐causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population. Hum Mutat 31:1–11, 2010. © 2010 Wiley‐Liss, Inc.     

High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG

Congenital deafness accounts for about 1 in 1000 infants and approximately 80% of cases are inherited as an autosomal recessive trait. Recently, it has been demonstrated that connexin 26 (GJB2) gene is a major gene for congenital sensorineural deafness. A single mutation (named 35delG) was found in most recessive families and sporadic cases of congenital deafness, among Caucasoids, with relative frequencies ranging from 28% to 63%. We present here the analysis of the 35delG mutation in 3270 random controls from 17 European countries. We have detected a carrier frequency for 35delG of 1 in 35 in southern Europe and 1 in 79 in central and northern Europe. In addition, 35delG was detected in five out of 376 Jewish subjects of different origin, but was absent in other non-European populations. The study suggests either a single origin for 35delG somewhere in Europe or in the Middle East, and the possible presence of a carrier advantage together with a founder effect. The 35delG carrier frequency of 1 in 51 in the overall European population clearly indicates that this genetic alteration is a major mutation for autosomal recessive deafness in Caucasoids. This finding should facilitate diagnosis of congenital deafness and allow early treatment of the affected subjects.     

Genealogy and geographical distribution of CFTR mutations in Saguenay Lac-Saint-Jean (Quebec,Canada)

Saguenay Lac-Saint-Jean (SLSJ), a region located in northeastern Quebec, has a high incidence of cystic fibrosis (CF). During the past few years the majority of the CF patients have been genotyped. The geographical distribution of the birth places of the patients and obligate carriers of the 621 + 1G → T, the A455E and the ΔF508 mutations (which accounted for 89% of the CF chromosomes) showed differences that can be explained by some degree of isolation but also by differential migration. The mean inbreeding and kinship coefficients were higher among the various CFTR mutation groups than in the general population. An ancestor couple common to most of the A455E carriers was identified. These data further substantiate the role of founder effect in the CF population of SLSJ.     

A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites

Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ～1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ～1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.     

Explanations for the discrepancy between variant frequency and homozygous disease occurrence: Lessons from Ashkenazi Jewish data

Ample data on recessive disorders among Ashkenazi Jews has been gathered and published through the years. The opportunity to integrate molecular records analyzed in actual affected individuals with data derived from population-documented frequencies enables to compare these figures.We reviewed assumed pathogenic variants reported among patients in the Israeli medical genetic database (IMGD) with a carrier frequency of 1% or more among Ashkenazi Jews in gnomAD. Among the 60 assumed pathogenic variants recorded in IMGD, 15 (25%) had either a disease incidence considerably lower than expected by the calculated carrier frequency (12 variants), or the variant was not characterized in Ashkenazi Jewish patients (three variants).Possible explanations for the rarity or absence of affected individuals despite high carrier frequency include embryonic lethality, clinical variability, and incomplete and age-related penetrance, in addition to the existence of additional assumed pathogenic variants on the founder haplotype, hypomorphic variants or digenic inheritance.The discrepancy in actual versus expected number of patients calls for caution upon designing and choosing targeted genes and recessive mutations for carrier screening.