Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews.

BACKGROUND: Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented. METHODS: Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals. RESULTS: We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. CONCLUSIONS: An Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.

[GENOTYPE-PHENOTYPE CORRELATIONS BY SPECIFIC FOUNDER VARIANTS IN BRCA IN ISRAELI WOMEN].

INTRODUCTION: Hereditary breast and ovarian cancer (HBOC) is predominantly accounted for by pathogenic variants (PVs) in BRCA1/BRCA2 genes. Population screening for recurring PVs in Ashkenazi Jews (AJ) was incorporated into the Israeli health basket in 2020, increasing the identification of BRCA carriers. Information on cancer risks for each PV in Israel is limited. AIMS: To assess genotype phenotype correlations of recurring BRCA PVs in Israeli carriers. METHODS: A retrospective cohort of 3,478 BRCA carriers followed-up in 12 medical centers, comprising the HBOC Consortium, formed the basis of the study. Data were collected using the electronic database, and analyzed by Chi square, t-tests and Kaplan-Meier survival analysis. RESULTS: Overall, 2145 BRCA1, 1131 BRCA2, and 22 double heterozygote PV carriers were analyzed. BRCA1 carriers had more cases of cancer (53.1% vs. 44.8%, p<0.001), ovarian cancer (OC) (17.1% vs. 10.6%, p<0.001), younger age at breast cancer (BC) (45.4 ±11.6SD years vs. 49.1 ±11.1SD years, p<0.001) and OC diagnosis (52.8 ±10.1SD yrs. vs. 61±10.6SD yrs. p<0.001), and more family history of BC (64.5% vs. 59.0%, p<0.001) and OC (36.7% vs. 27.3%, p<0.001) compared with BRCA2 carriers. Carriers of BRCA15382insC had more BC and less OC than BRCA1185delAG: 46.4% vs. 38.6% and 12.9% vs. 17.6% (p<0.04), respectively. CONCLUSIONS: In our population, similar to others, BRCA1 carriers have higher cancer rates and earlier age at diagnosis compared with BRCA2 carriers. The two recurring BRCA1 PVs have different risks: 5382insC carriers had more BC; 185delAG carriers had more OC. Risk-reducing measures should be based on variant-specific cancer risk.

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.

BACKGROUND: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. METHOD: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. RESULTS: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer). CONCLUSION: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers.

The yield of targeted genotyping for the recurring mutations in BRCA1/2 in Israel.

BACKGROUND: Hereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations-first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing. METHODS: Clinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other. RESULTS: Overall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained. CONCLUSIONS: The currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.

Mutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenita.

OBJECTIVE: We studied a series of patients with fetal akinesia deformation sequence (FADS)/arthrogryposis multiplex congenita (AMC), with nemaline bodies on muscle specimens, which revealed mutations in the NEB gene. METHOD: We pathologically assessed seven cases from three families, who presented with AMC/FADS. Targeted genetic analysis for Ashkenazi Jewish mutation (in relevant patients) was followed by next-generation sequencing and multiplex ligation-dependent probe amplification. RESULTS: All cases were detected on prenatal ultrasound. Characteristic nemaline bodies on muscle specimens were demonstrated in at least one case in each of the nuclear families. In the Ashkenazi Jewish family, the known founder mutation was compounded by one recurrent novel splice site. The other two families were of Chinese and Korean origins, and only one pathogenic heterozygous mutation was detected in each. CONCLUSIONS: Nemaline myopathy due to NEB mutation(s) leads to FADS/AMC. Currently, mutated NEB is under-recognized as a cause for AMC/FADS. Our study attempts to raise recognition of this gene as a cause, suggesting the NEB gene should be included in genetic panels used for FADS/AMC cases and be fully covered when EXOME sequencing is utilized. A heterozygous mutation may suggest either compounding undetected one or digenic interaction that requires further genetic analyses. © 2016 John Wiley & Sons, Ltd.

A Homozygous Nme7 Mutation Is Associated with Situs Inversus Totalis.

We investigated the cause of situs inversus totalis (SIT) in two siblings from a consanguineous family. Genotyping and whole-exome analysis revealed a homozygous change in NME7, resulting in deletion of an exon causing an in-frame deletion of 34 amino acids located in the second NDK domain of the protein and segregated with the defective lateralization in the family. NME7 is an important developmental gene, and NME7 protein is a component of the γ-tubulin ring complex. This mutation is predicted to affect the interaction of NME7 protein with this complex as it deletes the amino acids crucial for the binding. SIT associated with homozygous deletion in our patients is in line with Nme7(-/-) mutant mice phenotypes consisting of congenital hydrocephalus and SIT, indicating a novel human laterality patterning role for NME7. Further cases are required to elaborate the full human phenotype associated with NME7 mutations.

Screening for germline mutations in breast/ovarian cancer susceptibility genes in high-risk families in Israel.

We evaluated the clinical utility of screening for mutations in 34 breast/ovarian cancer susceptibility genes in high-risk families in Israel. Participants were recruited from 12, 2012 to 6, 2015 from 8 medical centers. All participants had high breast/ovarian cancer risk based on personal and family history. Genotyping was performed with the InVitae™ platform. The study was approved by the ethics committees of the participating centers; all participants gave a written informed consent before entering the study. Overall, 282 individuals participated in the study: 149 (53 %) of Ashkenazi descent, 80 (28 %) Jewish non-Ashkenazi descent, 22 (8 %) of mixed Ashkenazi/non-Ashkenazi origin, 21 (7 %) were non-Jewish Caucasians, and the remaining patients (n = 10-3.5 %) were of Christian Arabs/Druze/unknown ethnicity. For breast cancer patients (n = 165), the median (range) age at diagnosis was 46 (22-90) years and for ovarian cancer (n = 15) 54 (38-69) years. Overall, 30 cases (10.6 %) were found to carry a pathogenic actionable mutation in the tested genes: 10 BRCA1 (3 non-founder mutations), 9 BRCA2 (8 non-founder mutations), and one each in the RAD51C and CHEK2 genes. Furthermore, actionable mutations were detected in 9 more cases in 4 additional genes (MSH2, RET, MSH6, and APC). No pathogenic mutations were detected in the other genotyped genes. In this high-risk population, 10.6 % harbored an actionable pathogenic mutation, including non-founder mutations in BRCA1/2 and in additional cancer susceptibility genes, suggesting that high-risk families should be genotyped and be assigned a genotype-based cancer risk.

Congenital myopathy is caused by mutation of HACD1.

Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.

Bitterness of glucose/galactose: novel mutations in the SLC5A1 gene.

Glucose galactose malabsorption (GGM) is a rare autosomal recessive disorder characterized by life-threatening osmotic diarrhea at infancy. When the intake of the offending sugars (namely, glucose, galactose and lactose) is ceased, the diarrhea promptly stops. Mutations in the SLC5A1 gene, encoding the sodium-glucose co-transporter located in the brush border of enterocytes, have been shown to cause the disease. More than 300 subjects of diverse origin have been reported worldwide, most of whom are a result of a consanguineous union. We examined 6 patients from 4 families presenting with complaints consistent with GGM and responsive to the appropriate fructose-based diet. Genomic DNA of the patients was polymerase chain reaction amplified for each of the 15 exons of the SLC5A1 gene and analyzed by nucleotide sequencing. The analysis lead to the identification of 2 novel mutations: a 1915 del C mutation, a frameshift mutation leading to a premature stop at codon 645; and a substitution missense mutation of T to C on nucleotide 947 (exon 9) causing a L316P substitution. In addition, G426R and C255W mutations previously described were identified; in both cases, the patients were shown to be homozygous and their parents heterozygous for the mutation. Of note, additional patients who underwent a similar evaluation at our center for suspected GGM did not show mutations in the SLC5A1 gene. Because the latter did not previously undergo a diagnostic algorithm in full, for instance, one that may consist of a glucose breath hydrogen test and an empiric attempt of a dietary switch to galactomin, we suggest that molecular genotyping of such patients should only follow such appropriate clinical evaluation.

[Prenatal diagnosis of triploidy: the experience of Assaf-Harofe Medical Center].

INTRODUCTION: Triploidy (69 chromosomes) is the most common chromosomal anomaly encountered in human gestation, occurring in 1% of all conceptions. Most triploidies abort spontaneously during the 1st trimester. In cases that last, it is usually associated with fetal distress that can Lead to many obstetric complications. OBJECTIVE: To assess the indications for prenatal karyotyping of triploidy during pregnancy in our medical center. METHODS: This retrospective cohort study involved all singleton pregnancies diagnosed or referred to our institute because of triploidy, during the years 1998-2011. RESULTS: There were 1879 cases of termination of pregnancies (TOPs). During this period 8 cases of triploidy were aborted. The main indications for prenatal karyotyping in our study group were abnormal sonographic findings during anomaly scans. In addition, in all of the triploidy cases, the NT test was normal. Also, the 1st or 2nd trimester serum markers tests for early diagnosis of trisomy 18 predicted all of the triploidy cases that performed the tests. DISCUSSION: Our findings corresponded with other studies and show that the 1st or 2nd trimester serum markers tests for early diagnosis of trisomy 18, can lead to identification of triploidy pregnancies. CONCLUSIONS: The routine screening tests applied in Israel INT, serum markers tests and 2nd trimester anomaly scans) were highly effective in the identification of triploidy pregnancies.

National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease.

Mitochondrial complex I deficiency is the most prevalent and least understood disorder of the oxidative phosphorylation system. The genetic cause of many cases of isolated complex I deficiency is unknown because of insufficient understanding of the complex I assembly process and the factors involved. We performed homozygosity mapping and gene sequencing to identify the genetic defect in five complex I-deficient patients from three different families. All patients harbored mutations in the NDUFAF3 (C3ORF60) gene, of which the pathogenic nature was assessed by NDUFAF3-GFP baculovirus complementation in fibroblasts. We found that NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits. Furthermore, we show that NDUFAF3 tightly interacts with NDUFAF4 (C6ORF66), a protein previously implicated in complex I deficiency. Additional gene conservation analysis links NDUFAF3 to bacterial-membrane-insertion gene cluster SecF/SecD/YajC and to C8ORF38, also implicated in complex I deficiency. These data not only show that NDUFAF3 mutations cause complex I deficiency but also relate different complex I disease genes by the close cooperation of their encoded proteins during the assembly process.

Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.

FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. Although polymorphisms within the first intron of the FTO gene have been associated with obesity, the physiological role of FTO remains unknown. Here we show that a R316Q mutation, inactivating FTO enzymatic activity, is responsible for an autosomal-recessive lethal syndrome. Cultured skin fibroblasts from affected subjects showed impaired proliferation and accelerated senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.

Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile, "9+2"-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.

Preimplantation genetic diagnosis (PGD) for SHOX-related haploinsufficiency in conjunction with trisomy 21 detection by molecular analysis.

PURPOSE: Development of a molecular PGD protocol for a male with an X-linked deletion in the SHOX gene region, located in the pseudoautosomal region of the X/Y chromosomes. Due to excessive recombination in this region, the deletion can be found in male offspring. METHODS: We developed a 13 marker multiplex fluorescent PCR protocol: 3 markers within the deleted SHOX region, 5 flanking markers, 3 informative markers on chromosome 21 (advanced maternal age) and 2 markers for sex determination. RESULTS: Of four embryos, two wild type males, diploid for chromosome 21 were transferred resulting in twin boys. One embryo was an affected female and another embryo was Turner. Amniocentesis confirmed the implanted embryos were males (46XY), with no recombinations. CONCLUSIONS: While many X-linked disorders can be analyzed by sexing, genes located in the pseudoautosomal regions have high XY recombination rates, requiring multiple markers to enable an accurate diagnosis.

Age at diagnosis of cancer in 185delAG BRCA1 mutation carriers of diverse ethnicities: tentative evidence for modifier factors.

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.

A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and less than 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has been roughly constant in size for at least 6000 years, it is possible that the mutations in the two families are identical by descent. If there were substantial fluctuations in the size of the Bedouin population, it is more likely that there were two independent mutations. Based on the available data, the population genetic analysis does not strongly favour one conclusion over the other.

Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: a change of concept required.

PURPOSE: Hereditary hemochromatosis has not been fully evaluated in the non-Ashkenazi population and is considered to be relatively rare. After ascertaining three unrelated hereditary hemochromatosis families of North African Jewish origin with the HFE C282Y/C282Y genotype, we evaluated the C282Y and H63D allele frequencies among the different Jewish ethnic groups in Israel, in particular North African Jews. METHODS: Data were collected from three Israeli Medical Centers. North African, Oriental, Yemenite, and Sephardic Jewish healthy individuals were assessed for the C282Y and H63D alleles. RESULTS: The C282Y allele frequency was 1.02% (6/586 chromosomes), and the H63D allele frequency was 13.82% (81/586 chromosomes) in the North African Jewish group. The C282Y allele was not detected in the other non-Ashkenazi groups. The H63D allele frequency was 12.5% (38/304 chromosomes) in Oriental Jews, 14.9% (14/94 chromosomes) in Yemenite Jews, and 9.3% (11/118 chromosomes) in Sephardic Jews. DISCUSSION: Hereditary hemochromatosis is underrecognized among North African Jews, who have carrier frequencies of 1/58 and 1/4 for C282Y and H63D, respectively. HFE-hereditary hemochromatosis is not rare among this population as currently thought and merits increased awareness to prevent endpoint disease. The frequent occurrence of beta-thalassemia trait and HFE-H63D in non-Ashkenazi Jews raises the possibility of genetic interactions contributing to iron overload when coinherited and requires further evaluation.

Mosaic compound heterozygosity of SHOX resulting in Leri-Weill dyschondrosteosis with marked short stature: implications for disease mechanisms and recurrence risks.

Mutations or deletions in the SHOX gene cause Leri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD) when present in heterozygous or homozygous form, respectively. A new class of enhancer deletions was identified 30-250 kb downstream of SHOX. We identified a female patient with marked short stature, mosaic for monosomy X in 31% of her lymphocytes, and findings consistent with LWD. Additional molecular studies demonstrated segregation of 17 polymorphic markers flanking and including the SHOX locus, spanning 328 kb of pseudoautosomal region 1 (PAR1) region. A deletion up to 10 kb residing 197 kb downstream of SHOX gene was detected, which was germinally transmitted from her clinically unaffected father. This was associated with post-zygotic mosaic loss of the normal maternal X-chromosome, evidenced by fluorescent fragment analysis. Since most patients with LMD with deletions downstream of SHOX gene also have SHOX mutations in trans, it may suggest these deletions are associated with a milder phenotype. Further studies are required to elucidate the role of the former region in disease etiology. Mutations should be sought in clinically non-affected family members because of the variable expressivity in hemizygous carriers, and cytogenetic evaluation should be considered to detect possible X-chromosome rearrangements underlying the haploinsufficiency for the PAR1 when deletion is detected by molecular analysis. Similarly, when LWD and marked short stature occur in a patient with mosaic Turner syndrome, the possibility of mutations in SHOX and the downstream of SHOX gene should be considered.