| Synpolydactyly (SPD, MIM186000, or syndactyly type2) is an autosomal dominant inherited malformation of the distal limbs. It is characterized by soft-tissue syndactyly between fingers3and4and between toes4and5with partial or complete digit duplication within the syndactylous web. The fifth-finger clinodactyly, camptodactyly, or brachydactyly, variable syndactyly of the second to fifth toes, and middle phalanx hypoplasia are also found to be associatated with SPD. Incomplete penetrance and variable expressivity both between and within affected families are common and involvement is often asymmetrical. From one to four limbs can be involved, and the severity of involvements ranges from partial skin syndactyly to complete reduplication of a digit, extending as far proximally as the metacarpals/tarsals.Three loci have been identified at chromosomes2q31,22q13.31, and14q11.2-q12, and have been designated as SPD1, SPD2,and SPD3, respectively. Of these, SPD1is caused by the mutations in the HOXD13gene on chromosome2q31. HOXD13is a member of the HOX family that encodes for a transcription factor with a crucial role in limb development. Typical SPD is caused by expansions of a15-residue poly-Alanine tract in the N-terminal region of HOXD13. Genotype-phenotype correlation suggests that short poly-Alanine repeats (i.e.,+7repeats) are associated with lower penetrance and expressivity, whereas long repeats (+10and more) are associated with higher penetrance and more severe disease. Furthermore, deletion and missense mutations within the HOXD13homeodomain have been also found to cause atypical forms of SPD, characterized by a distinctive foot phenotype, brachydactyly-polydactyly or brachydactyly types D and E. Detection of SPD by prenatal diagnosis may be especially relevant in pregnancies at risk for severe affected individuals. To date, only few cases of prenatal diagnosis of SPD have been reported. Here, we present the clinical findings, genetic counseling, and prenatal diagnosis in a Chinese family. The family contains9affected. Linkage analysis mapped the disease locus to chromosome2q31where HOXD13located. Mutation analysis identified a9-residue poly-Alanine tract expansion in the N-terminal of HOXD13. Mid-trimester ultrasound and aminocentesis excluded that the fetus affected with SPD. Part1Phenotype and pedigree analysis of a large Chinese family with synpolydactylyA28-year-old woman with SPD from a large SPD kindred was referred for genetic counseling and prenatal diagnosis. She was born with severe bilateral hand-and foot abnormalities. She had complete syndactyly between the third and fourth fingers, and syndactyly between toes4th and5th with an extra toe at her feet. After we got the approval of the Ethics Committee of Shandong University School of Medicine, and informed consents from all participants, we performed clinical examination of the family members and obtained blood samples for linkage analysis and mutation detection. Further investigation of this family revealed8other family members with hand-and/or foot abnormalities: bilateral3/4syndactyly was noted in individuals â…£-12, â…£-14, â…¢-11, â…¢-15, V-4, IV7, and IV-6, unilateral syndactyly in indivudual â…¢-10. In the feet, the most obvious malformation was variable degrees synpolydactyly between toes4and5with an extra toe. Moreover, most of affected feet had additional metatarsal between fourth and fifth metatarsals. This is not commonly observed in other families. Compared with the previously reported patients, the patients in this family had more severe phenotypes at their feet. The disease phenotype in this kindred clearly followed a pattern of autosomal dominant inheritance, though with variable expressivity.Part2Linkage analysis and mutation detectionBecause mutations were identified in the HOXD13gene in several unrelated Chinese families with SPD, we conducted a linkage analysis with previously used markers flanking the HOXD13gene. Blood samples were obtained from16family members (9affected,7unaffected), and leukocyte genomic DNA was extracted via standard techniques. Using two markers (D2S1238, and D2S1245) spanning the HOXD13gene, we showed that SPD was linked to chromosome2q31. These results suggested that the HOXD13gene was a candidate for the SPD phenotype in this family. Therefore, we carried out the mutation detection by directly sequencing HOXD13gene. We identified a heterozygous27-bp expansion in the imperfect GCN triplet-repeat of exon1, c.184210dup. This mutation resulted in an addition of9alanine residues between the14th and15th alanine of the normally15-amino-acid-long poly-Alanine tract. This expansion represents a perfect duplication of the sixth to fourteenth triplet of the wild-type sequence. PCR amplification of the corresponding products comprising part of exon1revealed that this mutation cosegregated with the disease phenotype in the family, confirming full penetrance.Part3Prenatal ultrasonographic and molecular diagnosisPrenatal diagnosis was requested by the proband. Previous studies have shown that reliable observation of all fingers is possibly made by ultrasound examination between13and19weeks of gestation. To verify the fetal hand development, ultrasound examinations were conducted at16-21weeks, and demonstrated fetal biometry consistent with dates and normal amniotic fluid volume. All fingers and toes appeared normal. No other anomalies were observed. As mentioned above, enoumous phenotypic variation exists in SPD patients, and such clinical variability makes a prenatal diagnosis based on sonography alone difficult. At the proband's request, her aminotic fluid sample was obtained by ultrasound-guided amniocentesis at18weeks of gestation. Linkage analysis and mutation detection confirmed that the fetus did not inherite the mutant allele from his affected mother. Pregnancy progressed uneventfully. At term a female infant was born. Normal limb development was confirmed.To conclude, accurate prenatal diagnosis of SPD can be performed by combing the ultrasound diagnosis and molecular analysis. |
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