22
Jun

7q21.3 Deletion

7q21.3 Deletion

Deletion of the q21 segment on the long arm of chromosome 7 causes a relatively rare type of limb malformation called ectrodactyly. Ectrodactyly, also called split-hand/foot malformation (SHFM), presents when there is a failure to maintain signaling or a portion of the apical ectodermal ridge during embryogenesis1. When this occurs, there may be an underdevelopment, malformation, or complete absence of median digits resulting in a claw-like appearance of the distal portions of the upper and lower limbs1,2. Clinically, individuals will present with features including monodactyl, syndactyly, aplasia or hypoplasia of the phalanges, metacarpals, or metatarsals2. While rare when looking at all chromosomal disorders, ectrodactyly is quite common in individuals with deletions of 7q21.

Individuals with 7q21 deletions have SHFM type 1 (SHFM1). A defining feature of this type of SHFM is the presence of prelingual deafness in 35% of patients, intellectual disability in 33% of patients, and craniofacial malformations in 35% of patients1. Recently, there has been an attempt to determine if there is a genotype-phenotype correlation when looking at overall deletion size and location and comparing it to whether or not a patient presents with deafness, intellectual disability, or craniofacial malformations. It has been suggested that deletions involving more distal regions of chromosome 7 more frequently result in hearing loss3.

It is important to note that not every individual with 7q21 deletions will present in the same way. SHFM1 has both reduced penetration and variable expressivity. This means, even within one family, there may be a great deal of variability in who is affected and to what extent4. It has also been suggested that 7q21 deletion presentations have a sex bias. It appears that the deletion has a higher penetrance in males, meaning more males present with clinical features, than compared to the penetrance that exists within females5.

The genetic etiology behind SHFM1 can be complex. Deletions, complex translocations, and point mutations in a gene called DLX5 have all been reported as identified causes3. It is thought that the genes DLX5 and DLX6 play the largest role in the development of clinical features due to their role as transcription factors that are necessary for epidermal morphogenesis and limb development2. However, cis-regulatory elements have also been identified in causing SHFM1. Exons 15 and 17 of the gene DYNC1I1, which is also located in the 7q21 region, are thought to be tissue-specific enhancers of the DLX5 and DLX6 genes2. Deletions of these exons cause dysregulation of DLX5 and DLX6 expression even if DLX5 and DLX6 are unaffected1. This interaction results in SHFM1.

References

1Tayebi N, Jamsheer A, Flöttmann, R, et al. (2014). Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families. Orphanet J Rare Dis, 9: 108.
2Lango Allen H, Caswell R, Xie W, et al. (2014). Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans. J Med Genet, 51(4): 264–267.
3Delgado S, & Velinov M. (2015). 7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance. Mol Cytogenet, 8:37.
4Rai A, Srivastava P, & Phadke SR. (2019). Deletion 7q21.2-q22.1 in a case with split hand-split foot malformation, sensorineuralhearing loss and intellectual disability: Phenotype subtypes and the correlation with genotypes. Eur J Med Genet, 62(12): 103597.
5Sowińska-Seidler A, Socha M, Szoszkiewicz A, et al. (2023). A genotype-phenotype correlation in split-hand/foot malformation type 1: further refinement of the phenotypic subregions within the 7q21.3 locus. Front Mol Biosci, 10:1250714.

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