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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

ABSTRACT: We describe an 18-month-old male (BAB7221)with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother (BAB7219), the fetus (BAB7218) and her later born son (BAB7221). This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother (BAB8247). High density custom aCGH detecting all 6 individuals in the family

ORGANISM(S): Homo sapiens

SUBMITTER: Shen Gu

PROVIDER: E-GEOD-75190 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.

Gu Shen S Posey Jennifer E JE Yuan Bo B Carvalho Claudia M B CM Luk H M HM Erikson Kelly K Lo Ivan F M IF Leung Gordon K C GK Pickering Curtis R CR Chung Brian H Y BH Lupski James R JR

Human mutation 20151202 2

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density mi ...[more]

PMID: 26549411

Similar Datasets

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation

Project description:We describe an 18-month-old male (BAB7221)with split-hand malformation. Custom high-density array and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother (BAB7219), the fetus (BAB7218) and her later born son (BAB7221). This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother (BAB8247).

2015-11-20 | GSE75190 | GEO

Ectrodactyly/split hand feet malformation.

Project description:Split-hand/split-foot malformation is a rare limb malformation with median clefts of the hands and feet and aplasia/hypoplasia of the phalanges, metacarpals and metatarsals. When present as an isolated anomaly, it is usually inherited as an autosomal dominant form. We report a case of autosomal recessive inheritance and discuss the antenatal diagnosis, genetic counseling and treatment for the malformation.

| S-EPMC2922631 | biostudies-other

Nonsyndromic Split-Hand/Foot Malformation: Recent Classification.

Project description:Split-hand/foot malformation (SHFM) is a genetic limb anomaly disturbing the central rays of the autopod. SHFM is a genetically heterogeneous disorder with variable expressivity inherited as syndromic and nonsyndromic forms. We provide an update of the clinical and molecular aspects of nonsyndromic SHFM. This rare condition is highly complex due to the clinical variability and irregular genetic inheritance observed in the affected individuals. Nonsyndromic SHFM types have been reviewed in terms of major molecular genetic alterations reported to date. This updated overview will assist researchers, scientists, and clinicians in making an appropriate molecular diagnosis, providing an accurate recurrence risk assessment, and developing a management plan.

| S-EPMC6997797 | biostudies-literature

Genetic analysis of a congenital split?hand/split?foot malformation 4 pedigree.

Project description:In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split?hand/split?foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG?to?CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen?2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X?ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly?ectodermal dysplasia?cleft syndrome and SHFM4.

| S-EPMC5983954 | biostudies-literature

Reconstruction of a Monodactylous Hand with Microsurgical Free Foot-to-Hand Transfer in Split-Hand/Split-Foot Malformation with Tibial Aplasia.

Project description:Split-hand/split-foot malformation with long bone deficiency (SHLFD syndrome) is a rare congenital disorder, which may be sporadic or autosomal dominant with incomplete penetrance. When complete tibial aplasia is seen, the mainstay of treatment is amputation and lower limb prosthesis. This rare constellation of congenital differences presents an opportunity for microsurgical free tissue transfer using the principle of "spare parts" to improve the functionality of the hand. We present a rare case of split-hand/split-foot malformation with a monodactylous right hand and complete tibial aplasia, treated with microsurgical free foot-to-hand transfer at the time of lower limb amputation, reconstructing key pinch. At the latest 8 months follow-up, the patient had no pain, active key pinch, and ambulated independently with prostheses. He was able to use his right hand independently for a number of daily activities, such as stacking blocks, drinking from a cup, and playing with toys.

| S-EPMC7159962 | biostudies-literature

Split-Hand Malformation in a 4-Year-Old Child.

Project description:Split-hand deformity is one of the milder manifestations of a congenital disorder called split-hand/split-foot malformation. We present a case of a 4-year-old child with split-hand malformation in his left hand since birth. A median cleft was present in the affected hand with absence of the 3rd and 4th digits, giving rise to a characteristic lobster-claw appearance. Functionality of the affected hand was modestly impaired. As none of the close family members of the patient had similar limb malformations, the deformity was postulated to arise most likely from a de novo mutation. The patient was discharged after the parents were provided with genetic counseling.

| S-EPMC5559908 | biostudies-other

Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.

Project description:Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus.

| S-EPMC1918225 | biostudies-other

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

Project description: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.

| S-EPMC1287102 | biostudies-literature

Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.

Project description:Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

| S-EPMC4718869 | biostudies-literature

Homozygous sequence variants in the WNT10B gene underlie split hand/foot malformation.

Project description:Split-hand/split-foot malformation (SHFM), also known as ectrodactyly is a rare genetic disorder. It is a clinically and genetically heterogeneous group of limb malformations characterized by absence/hypoplasia and/or median cleft of hands and/or feet. To date, seven genes underlying SHFM have been identified. This study described four consanguineous families (A-D) segregating SHFM in an autosomal recessive manner. Linkage in the families was established to chromosome 12p11.1-q13.13 harboring WNT10B gene. Sequence analysis identified a novel homozygous nonsense variant (p.Gln154*) in exon 4 of the WNT10B gene in two families (A and B). In the other two families (C and D), a previously reported variant (c.300_306dupAGGGCGG; p.Leu103Argfs*53) was detected. This study further expands the spectrum of the sequence variants reported in the WNT10B gene, which result in the split hand/foot malformation.

| S-EPMC5901503 | biostudies-literature

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