Identification of Critical Region Responsible for Split Hand/Foot Malformation Type 3 (SHFM3) Phenotype through Systematic Review of Literature and Mapping of Breakpoints Using Microarray Data
Abstract:Split hand/foot malformation (SHFM) is a limb malformation with underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. There are six types of SHFM. Here, we report a boy with SHFM type 3 having normal 4th and 5th digits, absent 2nd and 3rd digits, and a 4th finger flexion deformity, as well as absent 2nd, 3rd and 4th toes bilaterally. His father, two paternal uncles, and two paternal first cousins have similar phenotype. Chromosome analysis sho… Show more
“…In 2015, Li et al identified the minimal critical region responsible for the SHFM3 phenotype in a series of 42 patients gathered from DECIPHER, previously published cases (PubMed) and a family with 6 affected individuals. Interestingly, they concluded that duplication of sequence in exon 1 of BTRC could be sufficient to the development of the SHFM3 phenotype and suggested that this may be via cis-acting or trans-acting effects on genes or regulatory sequences involved in the limb development pathway [26]. It is also interesting that patients harbouring wider duplications might also present with other limb malformations such as bilateral femoral hypoplasia but no SHFM [27].…”
Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.
“…In 2015, Li et al identified the minimal critical region responsible for the SHFM3 phenotype in a series of 42 patients gathered from DECIPHER, previously published cases (PubMed) and a family with 6 affected individuals. Interestingly, they concluded that duplication of sequence in exon 1 of BTRC could be sufficient to the development of the SHFM3 phenotype and suggested that this may be via cis-acting or trans-acting effects on genes or regulatory sequences involved in the limb development pathway [26]. It is also interesting that patients harbouring wider duplications might also present with other limb malformations such as bilateral femoral hypoplasia but no SHFM [27].…”
Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.
“…Furthermore, duplication of the homologous gene BTRC (MIM: 603482 ) is implicated in split hand-foot malformation. 9 Moreover, FBXW11 participates in the Wnt/β-catenin signaling pathway, 10 , 11 which is fundamentally important in eye and brain development 12 , 13 and digit patterning. 14 Figure 1 Phenotypes of Individuals 1, 2, 4, 5, and 7 (A–C) Individual 1 at age 13 years, showing bilateral ptosis related to the underlying ocular anomalies (A), contractures affecting the distal interphalangeal joints of the left 4 th and 5 th fingers (B), and a wide sandal gap, short terminal phalanges, contractures affecting the 4 th and 5 th toes, 2–3 toe syndactyly, and scarring from surgery removing the left supernumerary toe (C).…”
Section: Main Textmentioning
confidence: 99%
“…Copy number gains encompassing BTRC are linked with developmental limb anomalies. 9 , 56 Drosophila with mutations in Slimb, the ortholog of both FBXW11 and BTRC , develop supernumerary limbs or ectopic legs and eye anomalies. 57 , 58 , 59 In mice, mutations of GLI transcription factors can cause multiple malformations, including polydactyly, anophthalmia, and coloboma.…”
The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have
de novo
missense
FBXW11
variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling.
FBXW11
encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions.
In situ
hybridization studies on human and zebrafish embryonic tissues demonstrate
FBXW11
is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish
FBXW11
orthologs
fbxw11a
and
fbxw11b
resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of
FBXW11
in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
“…Both siblings were homozygous for this variant, demonstrating the effectiveness of this approach for identifying the underlying genetic phenomena in disorders like this. Another paper in this Special Issue also demonstrated the use of SNP microarrays in analyzing a rare condition, namely split-hand/foot malformation (SHFM) [7]. This condition affects one in 8500–25,000 newborns, with characteristic limb malformations of hands and feet.…”
The papers published in this Special Issue “SNP arrays” (Single Nucleotide Polymorphism Arrays) focus on several perspectives associated with arrays of this type. The range of papers vary from a case report to reviews, thereby targeting wider audiences working in this field. The research focus of SNP arrays is often human cancers but this Issue expands that focus to include areas such as rare conditions, animal breeding and bioinformatics tools. Given the limited scope, the spectrum of papers is nothing short of remarkable and even from a technical point of view these papers will contribute to the field at a general level. Three of the papers published in this Special Issue focus on the use of various SNP array approaches in the analysis of three different cancer types. Two of the papers concentrate on two very different rare conditions, applying the SNP arrays slightly differently. Finally, two other papers evaluate the use of the SNP arrays in the context of genetic analysis of livestock. The findings reported in these papers help to close gaps in the current literature and also to give guidelines for future applications of SNP arrays.
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