Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus.

Orientals are at higher risk for cleft lip with or without cleft palate (CL +/- P) than Caucasians or blacks. We collected demographic and family data to study factors contributing to the etiology of CL +/- P in Shanghai. The birth incidence of nonsyndromic CL +/- P (Shanghai 1980-87) was 1.11/1,000, with a male/female ratio of 1.42. Almost 2,000 nonsyndromic CL +/- P probands were ascertained from individuals operated on during the years 1956-83 at surgical hospitals in Shanghai. Detailed family histories and medical examinations were obtained for the probands and all available family members. Genetic analyses of the probands' families were performed under the mixed model with major locus (ML) and multifactorial (MFT) components. The hypotheses of no familial transmission and of MFT alone could be rejected. Of the ML models, the autosomal recessive was significantly most likely and was assumed for testing three complex hypotheses: (1) ML and sporadics; (2) ML and MFT; (3) ML, MFT, and sporadics. None of the complex models were more likely than the ML alone model. In conclusion, the best-fitting, most parsimonious model for CL +/- P in Shanghai was that of an autosomal recessive major locus.     

CD4 and CD8 T lymphocyte inheritance. Evidence for major autosomal recessive genes

The CD4/CD8 ratio has long been used for the follow-up and monitor of many infectious diseases. Following the demonstration in 1983 that the CD4/CD8 ratio in the mouse is under genetic control, it was subsequently shown to be controlled by a major locus in man. To define the mode of inheritance of the CD4/CD8 ratio, we addressed the absolute number of CD4 and CD8 cells in a large unselected control sample and in members of 70 nuclear families. Pedigrees of nuclear families were analyzed by complex segregation analysis. Data was adjusted prior to this analysis to remove the effects of relevant covariates. The non-genetic-transmission and the multifactorial model could be easily rejected for both CD4 and CD8 cells. Among the different inheritance models, involving both a major gene and a multifactorial (MFT) component, a major autosomal recessive gene with a residual MFT effect controlling the high number of CD4 and a major autosomal recessive gene with a residual MFT effect controlling the high number of CD8 cells were the significantly best-fitting ones. Our findings have some practical implications. Among all, the knowledge of the CD4+ cell number and the proportion between CD4+ and CD8+ T cells could be a useful parameter in predicting human immunodeficiency virus infection outcome.     

Inheritance of harelip and cleft palate in man

Summary The observations ofBirkenfeld, Schröder and ofSanders on harelip and cleft palate in man can be arranged in such a way that they all support the hypothesis that the trait is inherited as a double recessive, one gene being autosomal and the other one sex-linked. This explains the fact that harelip is twice as common in the male sex as it is in the female.With 1 plate     

Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa.

Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal dominant retinitis pigmentosa. The availability of a unique inbred Dutch pedigree has enabled us to address this question. We have used an intragenic polymorphism to exclude the possibility that a mutation in the rhodopsin gene is responsible for the disease in this patient population. These data provide evidence for the involvement of at least two loci in autosomal recessively inherited retinitis pigmentosa.     

Evidence of a third locus in X-linked recessive spastic paraplegia

We have investigated a family with severe X-linked spastic paraplegia and assigned the disease locus to Xq11.2-q23 by linkage and haplotype analysis. This region harbors the gene coding for proteolipid protein, which is mutated in one of the two established forms of X-linked spastic paraplegia, i.e., SPG2. We have performed extensive mutation analysis of this gene. Our failure to detect a mutation in this family suggests a third locus in X-linked recessive spastic paraplegia. Received: 7 March 1997 / Accepted: 14 April 1997     

Evidence of a sex-dependent association between the MSX1 locus and nonsyndromic cleft lip with or without cleft palate in the Chilean population

Prior studies have implicated an involvement of the Msx1 homeobox gene in cleft palate in mice and its homolog in humans (called MSX1 in the HOX7 gene, located on chromosome 4). In this study we present evidence of a sex-dependent association between MSX1 and non-syndromic cleft lip/palate (NSCLP) in the Chilean population. The sample included 73 NSCLP cases, 37 from multiplex families (Mx), 36 from simplex families (Sx), and 87 controls. Polymerase chain reaction amplification of the MSX1 intragenic microsatellite (CA)n-sequence shows significant (p = 0.035) differences in the allele frequencies between NSCLP-Mx males and control males. These differences are mainly due to frequency differences in allele *2 (173 base pairs) among cases (21.9%) and controls (13.2%). When the NSCLP cases are subdivided by sex and positive family history (Mx versus Sx), the Mx males (27.8%) as well as the total NSCLP-Mx cases (25.7%) showed significantly higher frequencies of allele *2, compared to controls (11.4% and 13.2%, respectively). Analysis of the genotype data indicates that the relative risk for NSCLP is greater for persons carrying allele *2 (i.e., odds ratio [OR] larger than 1), reaching significance for all Mx cases (OR = 2.67; 95% confidence interval [CI], 1.10 to 6.52) and even more pronounced for Mx males (OR = 3.33; 95% CI, 1.08 to 10.32). Taken together, these findings support the hypothesis that the genetic variation at the MSX1 locus is a predisposing gene involved in sex-dependent susceptibility to clefting and that it also differentiates simplex from multiplex families.     

Molecular genetic analysis of recessive mutations at a heterozygous autosomal locus in human cells

We have investigated the genotypic changes that lead to expression of a recessive allele at a heterozygous autosomal locus in a human cell line. Mutant clones lacking thymidine kinase activity were derived from a B-cell lymphoblastoid line initially heterozygous at the tk locus, and restriction mapping was performed to detect intragenic structural alterations in the tk gene. In addition, informative molecular markers located elsewhere on chromosome 17 were analysed in order to detect large-scale (multilocus) events. We report that among 325 spontaneous and induced mutants, allele loss was more common than intragenic rearrangements or point mutations; in many cases, loss of heterozygosity appears to have extended well beyond the locus under selection. Cytogenetic analysis of a subset of these mutants showed that expression of the recessive TK-deficient phenotype and the associated loss of heterozygosity for chromosome 17 markers was not typically associated with detectable chromosomal changes.     

Allelic and locus heterogeneity in autosomal recessive gelatinous drop-like corneal dystrophy

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disease characterized by the deposition of amyloid beneath the corneal epithelium and by severely impaired visual acuity leading to blindness. Although gelatinous corneal dystrophy has previously been mapped to chromosome 1p and seems to be associated with mutations in the M1S1 gene, molecular genetic studies have been limited to Japanese patients. To investigate the cause of GDLD in patients with diverse ethnic backgrounds, we performed linkage analyses in eight unrelated GDLD families from India, USA, Europe, and Tunisia. In seven of these families, the disease locus mapped to a 16-cM interval on the short arm of chromosome 1 between markers D1S519 and D1S2835, a region including the M1S1 gene. In addition, a 1.2-kb fragment containing the entire coding region of M1S1 gene was sequenced in affected individuals. Seven novel mutations (M1R, 8-bp ins., Q118 E, V194 E, C119 S, 870delC, and 1117delA) were identified in six families and two unrelated individuals. No sequence abnormalities were detected in a single family in which the GDLD locus was also excluded from the M1S1 region by linkage analysis. These findings demonstrate allelic and locus heterogeneity for GDLD.     

A locus for isolated cleft palate, located on human chromosome 2q32.

We present evidence for the existence of a novel chromosome 2q32 locus involved in the pathogenesis of isolated cleft palate. We have studied two unrelated patients with strikingly similar clinical features, in whom there are apparently balanced, de novo cytogenetic rearrangements involving the same region of chromosome 2q. Both children have cleft palate, facial dysmorphism, and mild learning disability. Their karyotypes were originally reported as 46, XX, t(2;7)(q33;p21) and 46, XX, t(2;11)(q33;p14). However, our molecular cytogenetic analyses localize both translocation breakpoints to a small region between markers D2S311 and D2S116. This suggests that the true location of these breakpoints is 2q32 rather than 2q33. To obtain independent support for the existence of a cleft-palate locus in 2q32, we performed a detailed statistical analysis for all cases in the human cytogenetics database of nonmosaic, single, contiguous autosomal deletions associated with orofacial clefting. This revealed 2q32 to be one of only three chromosomal regions in which haploinsufficiency is significantly associated with isolated cleft palate. In combination, our data provide strong evidence for the location at 2q32 of a gene that is critical to the development of the secondary palate. The close proximity of these two translocation breakpoints should also allow rapid progress toward the positional cloning of this cleft-palate gene.     

A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3.

Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.     

Assignment of a novel locus for autosomal recessive congenital ichthyosis to chromosome 19p13.1-p13.2

Autosomal recessive congenital ichthyosis (ARCI) is a rare, clinically and genetically heterogeneous genodermatosis. One gene (transglutaminase 1, on 14q11) and one additional locus (on 2q33-35, with an unidentified gene) have been shown to be associated with a lamellar, nonerythrodermic type of ARCI. We performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on five affected individuals from one large Finnish family with nonerythrodermic, nonlamellar ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on chromosome 19p13.1-2. The maximum two-point LOD score of 7.33 was obtained with the locus D19S252, and multipoint likelihood calculations gave a maximum location score of 5.2. The affected individuals share two common core haplotypes, which makes compound heterozygosity possible. The novel disease locus is the third locus linked to ARCI, supporting previous evidence for genetic heterogeneity of ARCI. This is also the first locus for a nonlamellar, nonerythrodermic phenotype of ARCI.     

A major locus for autosomal recessive retinitis pigmentosa on 6q, determined by homozygosity mapping of chromosomal regions that contain gamma-aminobutyric acid-receptor clusters.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, with extensive allelic and nonallelic genetic heterogeneity. Autosomal recessive RP (arRP) is the most common form of RP worldwide, with at least nine loci known and accountable for approximately 10%-15% of all cases. Gamma-aminobutyric acid (GABA) is the major inhibitory transmitter in the CNS. Different GABA receptors are expressed in all retinal layers, and inhibition mediated by GABA receptors in the human retina could be related to RP. We have selected chromosomal regions containing genes that encode the different subunits of the GABA receptors, for homozygosity mapping in inbred families affected by arRP. We identify a new locus for arRP, on chromosome 6, between markers D6S257 and D6S1644. Our data suggest that 10%-20% of Spanish families affected by typical arRP could have linkage to this new locus. This region contains subunits GABRR1 and GABRR2 of the GABA-C receptor, which is the effector of lateral inhibition at the retina.     

A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31

Primary microcephaly is a genetic disorder in which an affected individual has a head circumference >3 SDs below the age- and sex-related mean. A small but apparently normally formed brain is the reason for the reduced head circumference, and, probably because of this, all affected individuals are mentally retarded. The condition is genetically heterogeneous, and four loci have already been identified. We now report a fifth locus, MCPH5, which is an 8-cM region mapping to chromosome 1q31, defined by the markers GATA135F02 and D1S1678.     

Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13

Myoclonic epilepsies with onset in infancy and childhood are clinically and etiologically heterogeneous. Although genetic factors are thought to play an important role, to date very little is known about the etiology of these disorders. We ascertained a large Italian pedigree segregating a recessive idiopathic myoclonic epilepsy that starts in early infancy as myoclonic seizures, febrile convulsions, and tonic-clonic seizures. We typed 304 microsatellite markers spanning the 22 autosomes and mapped the locus on chromosome 16p13 by linkage analysis. A maximum LOD score of 4.48 was obtained for marker D16S3027 at recombination fraction 0. Haplotype analysis placed the critical region within a 3.4-cM interval between D16S3024 and D16S423. The present report constitutes the first example of an idiopathic epilepsy that is inherited as an autosomal recessive trait.     

An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of severe inherited childhood deafness. We present the linkage analysis of two inbred Bedouin kindreds from Israel that are affected with ARNSHL. A rapid genomewide screen for markers linked to the disease was performed by using pooled DNA samples. This screen revealed evidence for linkage with markers D9S922 and D9S301 on chromosome 9q. Genotyping of individuals from both kindreds confirmed linkage to chromosome 9q and a maximum combined LOD score of 26.2 (recombination fraction [theta] .025) with marker D9S927. The disease locus was mapped to a 1.6-cM region of chromosome 9ql3-q2l, between markers D9S15 and D9S927. The disease segregates with a common haplotype in the two kindreds, at markers D9S927, D9S175, and D9S284 in the linked interval, supporting the hypothesis that both kindreds inherited the deafness gene from a common ancestor. Although this nonsyndromic-hearing-loss (NSHL) locus maps to the same cytogenetic interval as DFNB7, it does not overlap the currently defined DFNB7 interval and may represent (1) a novel form of NSHL in close proximity to DFNB7 or (2) a relocalization of the DFNB7 interval to a region telomeric to its reported location. This study further demonstrates that DNA pooling is an effective means of quickly identifying regions of linkage in inbred families with heterogeneous autosomal recessive disorders.