Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion.

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.     

X-Chromosomally inherited split-hand/split-foot anomaly in a Pakistani kindred

Summary A Pakistani kindred comprising seven generations and 36 members with the split-hand/split-foot anomaly is described. The full expression of the trait, monodactylous or split hand and split foot, mainly of the lobster-claw type, was present in 33 males and 3 females. Other females showed a distinctly milder expression of the trait, usually in the form of partial syndactyly, metacarpal and phalangeal hypoplasia, and malformation. The distribution of the affected members in the pedigree is compatible with X-chromosomal inheritance. Hemizygous males and presumably homozygous females exhibit the typical split-hand/split-foot anomaly, whereas only a part of the obligatory heterozygous females show the milder expression. There were no associated anomalies, such as ectodermal dysplasia, cleft lip/palate, macular degeneration, malformations of the long bones or internal organs, and overt mental retardation.     

Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.     

Aplasia of tibia with split-hand/split-foot deformity. Report of six families with 35 cases and consideration about variability and penetrance

Summary Six families with a total of 34 affected persons with the syndrome of tibial aplasia and ectrodactyly are reported. The spectrum of malformations is compared to that of 99 familial cases from the literature. The full-blown syndrome consists of bilateral aplasia of tibiae and split-hand/split-foot deformity. Additional malformations may be distal hypoplasia or bifurcation of femora, hypo- or aplasia of ulnae, and minor anomalies such as aplasia of patellae, hypoplastic big toes, postaxial and intermediate polydactyly in connection with split-hand deformity, and cup-shaped ears. The mildest visible manifestation may be hypoplastic big toes, the severest is tetramonodactyly or transverse hemimelia. This disorder is autosomal dominantly inherited. The penetrance is markedly reduced.     

Genomewide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1

Split-hand/foot malformation with long-bone deficiency (SHFLD) is a rare, severe limb deformity characterized by tibia aplasia with or without split-hand/split-foot deformity. Identification of genetic susceptibility loci for SHFLD has been unsuccessful because of its rare incidence, variable phenotypic expression and associated anomalies, and uncertain inheritance pattern. SHFLD is usually inherited as an autosomal dominant trait with reduced penetrance, although recessive inheritance has also been postulated. We conducted a genomewide linkage analysis, using a 10K SNP array in a large consanguineous family (UR078) from the United Arab Emirates (UAE) who had disease transmission consistent with an autosomal dominant inheritance pattern. The study identified two novel SHFLD susceptibility loci at 1q42.2-q43 (nonparametric linkage [NPL] 9.8, P=.000065) and 6q14.1 (NPL 7.12, P=.000897). These results were also supported by multipoint parametric linkage analysis. Maximum multipoint LOD scores of 3.20 and 3.78 were detected for genomic locations 1q42.2-43 and 6q14.1, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of the SHFLD loci to a region of approximately 18.38 cM (8.4 Mb) between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43 and to a region of approximately 1.96 cM (4.1 Mb) between rs623155 and rs1547251 on 6q14.1. The study identified two novel loci for the SHFLD phenotype in this UAE family.     

Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin

The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.     

Exceptional complex chromosomal rearrangement and microdeletions at the 4q22.3q23 and 14q31.1q31.3 regions in a patient with azoospermia

In this report we describe the first patient ever found to have azoospermia in association with both exceptional complex chromosomal rearrangements and microdeletions at two translocation breakpoints. A 36-year-old male who had been suffering from male factor infertility was admitted to our clinic. The patient also displayed mild dysmorphia. An analysis of the patient's semen revealed azoospermia. GTG banding revealed the presence of an exceptional complex chromosomal rearrangement involving chromosomes 1, 4, 10 and 14. Using subtelomeric FISH analysis, the patient's karyotype was designated as 46,XY,t(1;10)(q43q44;q21q26.1)(CEB108/T7+,D1S3738-;10PTEL006+,D10S2290+, D1S3738+), ins(14;4) (q31.3;q23q33)(D14S1420+; D4S3359+, D4S2930+). Array-CGH analysis revealed two microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions. We suggest that microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions associated with both an exceptional complex chromosomal rearrangement and the Homo sapiens chromosome 4 open reading frame 37 (C4orf37) gene located at the 4q22.3q23 region might be associated with male factor infertility.     

Two new cases of trisomy 10q21 to 10qter in two sisters due to paternal translocation t(9;10) (q34;q24)]

Two sisters with multiple congenital malformations were shown to be trisomic for 10q24 to 10qter as a consequence of malsegregation of the balanced paternal translocation t(9;10) (q34;q24). Comparison of their phenotype with that of other patients reported in the literature confirms the individuality of the partial 10q trisomy syndrome.     

A whole-genome scan for 24-hour respiration rate: a major locus at 10q26 influences respiration during sleep

Identification of genes causing variation in daytime and nighttime respiration rates could advance our understanding of the basic molecular processes of human respiratory rhythmogenesis. This could also serve an important clinical purpose, because dysfunction of such processes has been identified as critically important in sleep disorders. We performed a sib-pair-based linkage analysis on ambulatory respiration rate, using the data from 270 sibling pairs who were genotyped at 374 markers on the autosomes, with an average distance of 9.65 cM. Uni- and multivariate variance-components-based multipoint linkage analyses were performed for respiration rate during three daytime periods (morning, afternoon, and evening) and during nighttime sleep. Evidence of linkage was found at chromosomal locations 3q27, 7p22, 10q26, and 22q12. The strongest evidence of linkage was found for respiration rate during sleep, with LOD scores of 2.36 at 3q27, 3.86 at 10q26, and 1.59 at 22q12. In a simultaneous analysis of these three loci, >50% of the variance in sleep respiration rate could be attributed to a quantitative-trait loci near marker D10S1248 at 10q. Genes in this area (GFRA1, ADORA2L, FGR2, EMX2, and HMX2) can be considered promising positional candidates for genetic association studies of respiratory control during sleep.     

De novo balanced translocation (2;10)(q24;q22) associated with mental retardation

We report a case of a reciprocal translocation between the long arms of the 2 and 10 chromosomes observed in a 14-year-old male with mild mental impairment, compulsive and obsessive behavior. The apparently balanced translocation was characterized by fluorescence in situ hybridization and the karyotype was 46, XY, t(2;10)(q24;q22). The way by balanced chromosomal translocations can lead to a disease phenotype are reviewed and discussed.     

Interstitial deletion of a chromosome 7 (q11.2q22.1) in a child with splithand/splitfoot malformation

Report on a 2-year-old, severely retarded girl with partial monosomy of 7q who exhibited not only features possibly due to the chromosomal aberration such as intrauterine dystrophy, microcephaly, odd facies, cleft palate, CHD, but also typical splithand/splitfoot malformation.