Consanguineous Cases Research Articles

The impact of consanguinity on the frequency of inborn errors of metabolism

Inborn errors of metabolism (IEM) are a heterogeneous group of genetic disorders present in all ethnic groups. We investigated the frequency of consanguinity among parents of newborns with IEM diagnosed by neonatal screening.Data were obtained from 15years of expanded newborn screening for selected IEM with autosomal recessive mode of inheritance, a national screening program of newborns covering the period from 2002 until April 2017. Among the 838,675 newborns from Denmark, the Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included in this study. These results were crosschecked against medical records. Information on consanguinity was extracted from medical records and telephone contact with the families.Among ethnic Danes, two cases of consanguinity were identified in 93 families (2.15%). Among ethnic minorities there were 20 cases of consanguinity among 33 families (60.6%). Consequently, consanguinity was 28.2 times more frequent among descendants of other geographic place of origin than Denmark. The frequency of consanguinity was conspicuously high among children of Pakistani, Afghan, Turkish and Arab origin (71.4%). The overall frequency of IEM was 25.5 times higher among children of Pakistani, Turkish, Afghan and Arab origin compared to ethnic Danish children (5.35:10,000 v 0.21:10,000). The frequency of IEM was 30-fold and 50-fold higher among Pakistanis (6.5:10,000) and Afghans (10.6:10,000), respectively, compared to ethnic Danish children.The data indicate a strong association between consanguinity and IEM. These figures could be useful to health professionals providing antenatal, pediatric, and clinical genetic services.

Clinical utility of the low-density Infinium QC genotyping Array in a genomics-based diagnostics laboratory

BackgroundWith 15,949 markers, the low-density Infinium QC Array-24 BeadChip enables linkage analysis, HLA haplotyping, fingerprinting, ethnicity determination, mitochondrial genome variations, blood groups and pharmacogenomics. It represents an attractive independent QC option for NGS-based diagnostic laboratories, and provides cost-efficient means for determining gender, ethnic ancestry, and sample kinships, that are important for data interpretation of NGS-based genetic tests.MethodsWe evaluated accuracy and reproducibility of Infinium QC genotyping calls by comparing them with genotyping data of the same samples from other genotyping platforms, whole genome/exome sequencing. Accuracy and robustness of determining gender, provenance, and kinships were assessed.ResultsConcordance of genotype calls between Infinium QC and other platforms was above 99%. Here we show that the chip’s ancestry informative markers are sufficient for ethnicity determination at continental and sometimes subcontinental levels, with assignment accuracy varying with the coverage for a particular region and ethnic groups. Mean accuracies of provenance prediction at a regional level were varied from 81% for Asia, to 89% for Americas, 86% for Africa, 97% for Oceania, 98% for Europe, and 100% for India. Mean accuracy of ethnicity assignment predictions was 63%. Pairwise concordances of AFR samples with the samples from any other super populations were the lowest (0.39–0.43), while the concordances within the same population were relatively high (0.55–0.61). For all populations except African, cross-population comparisons were similar in their concordance ranges to the range of within-population concordances (0.54–0.57). Gender determination was correct in all tested cases.ConclusionsOur results indicate that the Infinium QC Array-24 chip is suitable for cost-efficient, independent QC assaying in the settings of an NGS-based molecular diagnostic laboratory; hence, we recommend its integration into the standard laboratory workflow. Low-density chips can provide sample-specific measures for variant call accuracy, prevent sample mix-ups, validate self-reported ethnicities, and detect consanguineous cases. Integration of low-density chips into QC procedures aids proper interpretation of candidate sequence variants. To enhance utility of this low-density chip, we recommend expansion of ADME and mitochondrial markers. Inexpensive Infinium-like low-density human chips have a potential to become a “Swiss army knife” among genotyping assays suitable for many applications requiring high-throughput assays.

Single nucleotide variant sequencing errors in whole exome sequencing using the Ion Proton System.

Errors in sequencing are a major obstacle in the interpretation of next-generation sequencing (NGS) results. In the present study, sequencing errors identified from analysis of single nucleotide variants (SNVs) identified during exome sequencing of human germline DNA were studied using the Thermo Fisher Ion Proton System. Two consanguineous cases were selected for sequencing using the AmpliSeq Exome capture kit, and SNVs found in both cases were validated using Sanger sequencing. A total of 98 SNVs detected by NGS were randomly selected for further analysis. Nine of the analyzed SNVs were shown to be false positives when confirmed by Sanger sequencing. All but one SNV were considered to be homopolymer regions, mainly through the insertion or deletion of nucleotides. The remaining error was considered to be related to the primer. The present results revealed that the majority of the SNV sequencing errors originated from homopolymer insertion/deletion errors, which are commonly observed when using the Ion Torrent system.

Mutations of IFT81, encoding an IFT-B core protein, as a rare cause of a ciliopathy

Results Homozygosity for IFT81 mutations were identified in two consanguineous sporadic cases. The first individual harbored a splice site change predicted to result in an inframe exon skipping; the second carried a 4 bp deletion resulting in a loss-of-stop with extension of the deduced protein by 10 amino acids. The spectrum of IFT81-related disease expression included nephronophthisis, retinal dystrophy, cerebellar atrophy, and polydactyly. Fibroblasts from one affected individual showed no difference to control cells with regard to IFT81 localization or binding to IFT25, but a statistically significant decrease in ciliated cell abundance was noted. GLI2 expression and ciliary localization were impaired suggesting altered sonic hedgehog signaling.

English

CONTEXT/BACKGROUND: Congenital malformations have been known and recognized for centuries. It is a stimulating problem for research because of the high frequency of their occurrence and the influence of consanguinity on these defects is even more devastating problem. AIM AND OBJECTIVES: To determine the effect of consanguinity in occurrence of congenital defects and occurrence of more common types of congenital defects. MATERIALS AND METHODS: The study was done retrospectively in Government medical college and civil hospitals between 1 st Oct. 2011 till 31 st May 2012. A total of 182 congenitally defective live births and still births admitted in above hospitals in same period were studied against total deliveries taken place. Information was collected by using questionnaires and pedegree charts were formed. Information about consanguinity, degree of consanguinity, type and subtype of anomaly etc. was obtained. Data obtained was statistically analysed and compared with previous studies. RESULTS: Incidence of congenital anomalies was 1.16%. Cardiovascular defects were the most common type of anomaly and atrial septal defect was most common subtype. Third degree / first cousins was the most common type of degree of consanguinity found amongst all. Male pre-ponderence was found amongst the anomalous births. Frequency of consanguineous marriages was found more in muslims than hindus. DISCUSSION AND CONCLUSIONS: 1. Births with congenital defects were commonly occurring among normal births and the incidence calculated was 1.79 % in the present study. 2. Cardiovascular defects were most common type of defects. 3. In the present study, it was found that third degree consanguinity cases were most common, about 56.25 % out of all 48 consanguineous cases. 4. In the present study congenital defects were found to occur more commonly in consanguineous unions than

Mutation screening of retinal dystrophy patients by targeted capture from tagged pooled DNAs and next generation sequencing.

PurposeRetinal dystrophies are genetically heterogeneous, resulting from mutations in over 200 genes. Prior to the development of massively parallel sequencing, comprehensive genetic screening was unobtainable for most patients. Identifying the causative genetic mutation facilitates genetic counselling, carrier testing and prenatal/pre-implantation diagnosis, and often leads to a clearer prognosis. In addition, in a proportion of cases, when the mutation is known treatment can be optimised and patients are eligible for enrolment into clinical trials for gene-specific therapies.MethodsPatient genomic DNA was sheared, tagged and pooled in batches of four samples, prior to targeted capture and next generation sequencing. The enrichment reagent was designed against genes listed on the RetNet database (July 2010). Sequence data were aligned to the human genome and variants were filtered to identify potential pathogenic mutations. These were confirmed by Sanger sequencing.ResultsMolecular analysis of 20 DNAs from retinal dystrophy patients identified likely pathogenic mutations in 12 cases, many of them known and/or confirmed by segregation. These included previously described mutations in ABCA4 (c.6088C>T,p.R2030*; c.5882G>A,p.G1961E), BBS2 (c.1895G>C,p.R632P), GUCY2D (c.2512C>T,p.R838C), PROM1 (c.1117C>T,p.R373C), RDH12 (c.601T>C,p.C201R; c.506G>A,p.R169Q), RPGRIP1 (c.3565C>T,p.R1189*) and SPATA7 (c.253C>T,p.R85*) and new mutations in ABCA4 (c.3328+1G>C), CRB1 (c.2832_2842+23del), RP2 (c.884-1G>T) and USH2A (c.12874A>G,p.N4292D).ConclusionsTagging and pooling DNA prior to targeted capture of known retinal dystrophy genes identified mutations in 60% of cases. This relatively high success rate may reflect enrichment for consanguineous cases in the local Yorkshire population, and the use of multiplex families. Nevertheless this is a promising high throughput approach to retinal dystrophy diagnostics.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Report of Seven Additional Sicilian Patients and Overview of the Overall Series from Sicily

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive inherited disease caused by the mutation of the AIRE gene on chromosome 21. To date, 8 Sicilian patients have been described and the R203X AIRE mutation was found to be the most common in this region. Aims: (1) To describe 7 additional Sicilian APECED patients and to review all 15 Sicilian APECED patients who have been investigated by our group in the last years, and (2) to report a novel AIRE gene mutation. Results: Among the 3 cardinal features of APECED, hypoparathyroidism has been already detected in all 15 patients, whereas Addison's disease and chronic mucocutaneous candidiasis have so far been found in 10/15 and 12/15 cases, respectively. In 2 consanguineous cases, AIRE gene analysis revealed a novel mutation, named IVS13+2T, in homozygosis. R203X was the most common mutation in this region (30% of alleles and 46.6% of patients), followed by R257X (20% of alleles and 40% of patients). Conclusions: Sicilian APECED patients are confirmed to have some peculiar characteristics from a clinical and genetic point of view. No correlations between genotype and phenotype were identified.

The suitability and attraction of the population of the United Arab Emirates for the study of genetic inheritance in scoliosis

Background Recently, significant advances have been made in understanding the aetiology of adolescent idiopathic scoliosis (AIS) in the area of genetic inheritance. Essential to the success of these studies is the finding of large families with several cases of AIS from which blood samples can be collected and analysed. The emirati culture is unique and encourages large families with many children, often several wives with the same husband, and many cases of consanguinity especially among first cousins. This complex family structure might very well be suited to provide more appropriate examples for the study of genetic heritage in AIS than the more typical western family. Material and methods The genealogical history of 15 extended emirati families was collected for 4 generations which would approximate that required for the study of AIS. The number of children in each family and the incidence of consanguinity among first cousins were calculated. These data were compared with similar, published data for western families. Results The average number of children per family among the emirati population was 6.29 (often >10), approximately 3x that of the average western family. In each family there were several examples of multiple wives and first cousin marriages. Two families were found in which at least one person had AIS. Conclusions These results suggest that the unique, well controlled structure of the emirati families lend themselves to being excellent for extensive study of the genetic inheritance aspects of the aetiology of AIS because of the greater familial component.

Birth defects observed with maternal carbimazole treatment: Six cases reported to Nice's Pharmacovigilance Center

Goals To report cases of embryopathy occurring following first trimester exposure to anti-thyroid drugs. Methods Retrospective screening of the database of our Pharmacovigilance Center from 1987 to date. Results We report six cases of embryopathy, all following carbimazole exposure during the first trimester: two cases of abdominal wall defect, including one associated with facial dysmorphia; one case of digestive malformation (patent omphalomesenteric duct); two cases of aplasia cutis including one with facial dysmorphism; one case of bilateral choanal atresia with aorta coarctation associated with poorly controlled insulin dependent diabetes. Four out of five patients were euthyroid with treatment during the first trimester. We found a context suggesting genetic predisposition to congenital malformation in three cases: two cases of parental cleft lip/palate, one case of consanguinity. Outcome was favorable in all cases. Conclusions We want to raise awareness about the potential teratogenicity of carbimazole, probably on a predisposed genetic background. We suggest better reporting of congenital anomalies in children of women with Graves’disease, with or without in utero exposure to anti-thyroid drugs. In light of current literature, propylthiouracil should be the first line treatment for hyperthyroid women wishing a pregnancy.

Harlequin ichthyosis: a review of 50 cases and update of ABCA12 mutation analysis

Mutations in the ABCA12 gene underlie the most severe form of recessive congenital ichthyosis, Harlequin ichthyosis (HI). Due to the rarity of cases, there are no large series reporting the outcomes of babies born with HI. To improve the care of HI families, the authors have established a major referral centre for HI genetic screening and conducted an international study of 50 children born with this condition. The aim of this study is to assess the clinical outcomes of patients with HI referred to us for ABCA12 analysis and thereby report neonatal complications and long-term sequelae. Secondly, this study aims to identify novel mutations to facilitate prenatal diagnosis. Referring physicians were asked to review medical notes and retrospectively complete a clinical questionnaire. Adults and children over five were asked to complete a dermatology life quality index (DLQI) questionnaire. Mutation analysis was performed using PCR and sequencing but in one consanguineous case, reverse transcriptase-PCR (RT-PCR) on a parental skin biopsy was performed, followed by copy number analysis. Fifty responses were received. All infants had a typical appearance at birth and thereafter developed a persistent, diffuse scaly erythema with hair thinning and nail deformities. In most cases, acitretin was started shortly after birth. Approximately 54% of neonates survived into childhood and beyond. Mortality was associated with respiratory distress and sepsis. Early childhood skin infections with Staphylococcus, Streptococcus, Pseudomonas and MRSA were reported in one third. Problems maintaining weight necessitating nasogastric feeding in infancy and a high-calorie diet thereafter were seen in 58%. Older children experienced joint pain and there were two cases of inflammatory arthritis. While most children attended a mainstream school, 57% in the UK needed statementing. Despite the severity of the disease, the average children9s DLQI score was only 10/30. Eight novel ABCA12 mutations were identified and another three patients have been shown to harbour the common Pakistani mutation 7322delC. In the consanguineous case, a deletion of exons 12–15 was detected by RT-PCR and subsequently confirmed using copy number analysis. This is the first large-scale study of HI and provides important prognostic information for clinicians and affected families.

Platform Highlights Session A 4:30 p.m.-6:00 p.m.

Abstract Samuel F. Berkovic 1,2 , L. M. Dibbens 3 , A. Oshlack 4 , J. D. Silver 4,5 , M. Katerelos 6 , D. F. Vears 1 , J. Stankovich 4,7 , E. Andermann 8 , F. Andermann 8 , B. L. Hodgson 3 , M. A. Bayly 3 , J. C. Mulley 3 , G. K. Smyth 4 , D. A. Power 2,6 and M. Bahlo 4 ( 1 Epilepsy Research Centre and Department of Medicine, University of Melbourne, Heidelberg West, VIC, Australia ; 2 Departments of Neurology and Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia ; 3 Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, SA, Australia ; 4 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia ; 5 Department of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia ; 6 Burnet Institute at Austin, Austin Health, Heidelberg, VIC, Australia ; 7 Menzies Research Institute, University of Tasmania, Hobart, TAS, Australia and 8 Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital McGill University, Montreal, QC, Canada ) Rationale: Action myoclonus renal failure (AMRF) syndrome is a lethal inherited form of progressive myoclonus epilepsy associated with renal failure. It typically presents at 15 – 25 years with neurological symptoms (tremor, action myoclonus, seizures and later ataxia), or proteinuria evolving into renal failure requiring dialysis or transplantation. The autosomal recessive gene defect underlying AMRF was unknown and the lack of large pedigrees and lethality of the disorder precluded a conventional mapping strategy. Methods: We studied three Australian patients and their families: case A of Turkish-Cypriot origin whose parents were first cousins, and cases B and C whose ancestors came from different regions of Britain and no inbreeding loops were known for either family. Using SNP chips and a novel mapping strategy, homozygosity mapping of a known consanguineous case was conducted and then combined with analysis of affected and unaffected siblings in the other families. Results: Homozygosity mapping using all three cases identified a 5.3 cM critical region on chromosome 4 and a second 3.0 cM region on chromosome 20. Microsatellite analysis in these regions excluded the chromosome 20 locus and leaving the chromosome 4 locus as the region of interest. Microarray expression analysis of the two living AMRF patients and their unaffected same sex siblings as controls identified a lysosomal protein as the likely candidate. Sequencing revealed mutations predicted to truncate the protein in all three patients and a subsequent family. Western blotting showed absent expression of this lysosomal membrane protein in lymphocytes. Conclusions: Using only 3 affected individuals, we have identified the gene for this rare form of progressive myoclonus epilepsy. This will allow for earlier diagnosis of this condition and provides new insights into the biology of this disorder. This work was supported by a grant from the Australian National Health and Medical Research Council.

La dyskinésie ciliaire primitive: Etude clinique et diagnostic

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function.We analyzed the main clinical features and test results of PCD in order to evaluate their usefulness for diagnosis.Retrospective study of 35 cases of PCD evaluated by the same team, with nasal brushings in all cases (special light microscopy) and electron microscopy and/or by isotopic mucociliary clearance study in some.In a cohort of 145 patients with suspected PCD, the diagnosis of PCD was established in 35 cases using a combination of compatible clinical features coupled with the study of nasal brushings: 13 females and 22 males, average age at time of diagnosis 25 years, situs inversus in 12 patients (34%).In the absence of consensus in the literature for diagnosis of PCD, we propose the association of the following diagnostic criteria: upper airway and bronchopulmonary infections beginning often early in the life, more inconstantly situs inversus, familial cases of PCD, consanguinity, infertility and permanent and ubiquitous abnormalities of ciliary structure/function. Nasal brushing with ciliary study (special light microscopy) seems to be an easy and reliable diagnostic criterion. Electron microscopy is necessary for proving ultrastructural abnormalities.

Amaurose congénitale de Leber : le point sur l’hétérogénéité génétique, actualisation de la définition clinique

Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium, but they are involved in strikingly different physiologic pathways, resulting in an unforeseeable pathophysiologic variety. This broad genetic and physiologic heterogeneity, which could greatly increase in the coming years, hinders molecular diagnosis in LCA patients. Genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here we report a comprehensive mutational analysis of all the known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% of patients. GUCY2D accounted for by far the largest part of the LCA cases in our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%) and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited in the search for phenotype variations. Genotype-phenotype correlations were found that made it possible to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. In addition, objective ophthalmologic data subdivided each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the onerous task of genotyping new patients, but only if the most precise clinical history since birth is available.

Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.

Restrictive dermopathy (RD), also called tight skin contracture syndrome (OMIM 275210), is a rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. We explored nine fetuses/newborns children with RD. Two were found to have an heterozygous splicing mutation in the LMNA gene, leading to the complete or partial loss of exon 11 in mRNAs encoding Lamin A and resulting in a truncated Prelamin A protein. Lamins are major constituents of the nuclear lamina, a filamentous meshwork underlying the inner nuclear envelope. In the other seven patients, a unique heterozygous insertion leading to the creation of a premature termination codon was identified in the gene ZMPSTE24, also known as FACE-1 in human. This gene encodes a metalloproteinase specifically involved in the post-translational processing of Lamin A precursor. In all patients carrying a ZMPSTE24 mutation, loss of expression of Lamin A as well as abnormal patterns of nuclear sizes and shapes and mislocalization of Lamin-associated proteins was evidenced. Our results indicate that a common pathogenetic pathway, involving defects of the nuclear lamina and matrix, is involved in all RD cases. RD is thus one of the most deleterious laminopathies identified so far in humans caused by (primary or secondary) A-type Lamin defects and nuclear structural and functional alterations.

Severe progressive form of congenital muscular dystrophy with calf pseudohypertrophy, macroglossia and respiratory insufficiency

A novel form of congenital muscular dystrophy in four unrelated patients is proposed. Congenital hypotonia, markedly increased CK, calf pseudohypertrophy and proximal weakness were common early findings. Two cases were severely affected since infancy and never walked. The phenotypical homogeneity was not very evident until advanced stages of the disease. All the patients showed catastrophic progression of the weakness, severe restrictive respiratory insufficiency, macroglossia, peculiar extreme amyotrophy of hands and feet, and a round and ‘puffy’ face. All patients became tetraplegic and required mechanical ventilation. Two cases had signs of mild cardiac involvement. The only non-tracheotomised patient died of respiratory complications. No mental retardation or specific brain abnormalities were observed. All patients showed secondary deficit of laminin α2 and up-regulation of laminin α5 in muscle. Expression of α-dystroglycan was severely reduced in two available muscle samples. The known loci for congenital muscular dystrophies were excluded in the only consanguineous case by linkage analysis. Clinical, immunohistochemical and genetic findings strongly suggest a distinct entity.

Sibling incest and formulation of paternity probability: case report

Paternity determination of a fetus whose mother was admitted to an institution for the welfare and health of handicapped persons was requested of us by a doctor and lawyer of the institution. The fetus was recovered by a legal artificial abortion based on the Act on Maternity Health and Welfare (Japan) with the permission of the custodian. Commercially available MCT118, HLADQA, PM, and 9 STRs were tested for DNA samples from the fetus, the mother, her younger brother, her father, her grandfather, and 4 staff members of the institution. Only the brother was not excluded and the paternity probability was estimated at 99.857% on the basis of newly formulated expressions for multiallelic loci on the assumption of sibling incest. We concluded then that the fetus was fathered by the brother. DNA fingerprinting with multilocus and single locus minisatellite probes which were performed to confirm the paternity also support the conclusion. Bandsharing frequencies between the family members, however, did not necessarily reflect their actual kinship, which findings suggest that multilocus DNA fingerprinting requires further accumulation of data for consanguineous cases such as incest. Universal formulation for calculating paternity probability for a sibling incest case on the basis of multiallelic monolocus polymorphisms is also presented.

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

Neural tube defects in the middle belt of Nigeria.

Forty-two babies were found to have neural tube defects during a 3-year prospective study in a large cosmopolitan West African city. An incidence of 7/1000 deliveries was noted. The commonest defect was meningomyelocele, in 45 per cent of cases. Other defects comprised anencephaly (5 per cent), Arnold-Chiari malformation (7 per cent), encephalocele (19 per cent), occipital meningocele (14 per cent) and spina bifida occulta (10 per cent). No case of consanguinity was encountered. More defects were found among females and low birth weight infants among those whose mothers were aged between 20 and 30 years, and in mothers with parity of four and above. The commonest associated defect was talipes equinus in 15/42 (36 per cent) infants. Developmental assessments (neurological follow-up status) done at the age of 18 months on five surviving cases of meningomyelocele showed very poor development.

Evidence for a major gene in familial anencephaly

A 21-year-old white woman sought counseling after the birth of two consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia. The presence of parental consanguinity prompted reconsideration of recessive inheritance. The segregation ratio from 23 additional consanguineous cases was compared with that observed in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the non-sporadic cases were consistent with a major autosomal recessive locus in both populations.

Segregation frequency in microcephaly

A total of 118 cases of microcephaly were clinically evaluated under two main groups: primary microcephaly (61 cases) and secondary microcephaly (57 cases). Secondary cases were generally characterized by convulsions, spasticity, and other congenital anomalies. Estimates of segregation frequency obtained separately in primary and secondary cases indicated that the primary consanguineous cases were most probably due to a single recessive gene. The segregation frequency was substantially less in other types, indicating much lower genetic risks in these cases.