7q21.3 Deletion involving enhancer sequences within the gene DYNC1I1 presents with intellectual disability and split hand-split foot malformation with decreased penetrance
© Delgado and Velinov. 2015
Received: 9 February 2015
Accepted: 12 May 2015
Published: 13 June 2015
Split hand-split food malformation (SHFM) is a congenital defect of limb development that involves the central rays of the autopod and presents with median clefts of the hands and feet. It often includes syndactyly and aplasia/hypoplasia of the phalanges. SHFM is a genetic condition with high genetic heterogeneity, with at least 6 associated chromosomal loci. A locus in chromosomal region 7q21.3, associated with SHFM is referred to as SHFM1. Genes considered to be associated with SHFM1 are DLX5 and DLX6. These two genes participate in the Wnt pathway that has a role in limb development. The gene DYNC1I1, located proximally (centromeric) to the SHFM1 locus was recently reported to include enhancer sequences involved in limb development in its exons 15 and 17. These sequences were shown to cis-regulate the function of the adjacent SHFM associated genes. We report a family, in which the father and three of his sons carry an approximately 1 Mb deletion in this chromosomal region, arr[hg19]7q21.3(94,769,383-95,801,045)x1. The deleted region is located proximally (centromerically) adjacent to the SHFM region at 7q21.3. It does not include the SHFM candidate genes DLX5 and DLX6, but includes the enhancer sequences within DYNC111 and six other genes centromeric to DYNC1I1. All deletion carriers have various degrees of intellectual disability while two of them have SHFM. This family is the eighth reported family where a chromosome 7q21.3 deletion co-segregating with SHFM involves the enhancer regions within gene DYNC111, but does not involve the genes DLX5 and DLX 6. This is also the third family where decreased penetrance of enhancer-associated SHFM is demonstrated. Intellectual disability was not observed in the previously reported families and may be associated with deficiency of one or more of the 6 genes included in the reported deletion centromeric to DYNC1I1.
Split hand-split foot malformation (SHFM), also referred to as ectrodactyly, is a group of genetic conditions affecting the limb formation. Limb defects associated with SHFM involve the central autopod and manifest as midline clefts of hands and/or feet. Six loci associated with SHFM were described to-date. Type 1 SHFM1 is associated with defects in chromosomal region 7q21.3 . Deletions, duplications and complex chromosomal rearrangements of this chromosomal region, as well as point mutations in the gene DLX5 located in the region were reported in individuals with SHFM1 [2–6]. Recently two enhancer sequences expressed in regions of limb development in mouse embryos were identified within the exons 15 and 17 of the gene DYNC1I1 that maps centromeric to DLX5/6. These enhancer sequences were shown to regulate the expression of DLX5/6 and thus have a role in embryonic limb development [7, 8]. Seven families with isolated or familial SHFM, who have deletions involving these enhancers but not the genes DLX5/6 were reported to-date [9–12]. In two of these reports decreased penetrance of these chromosomal aberrations was demonstrated [9, 12]. In one of these reports Rattanasopha et al. also showed maternal imprinting of the genes DLX5 and 6 in osteoblasts . We report an additional family where four relatives carry a 7q21.3 deletion involving DYNC1I1 and 6 other proximally located genes. The carriers of this deletion have SHFM with reduced penetrance and intellectual disability.
Oligo SNP array, Affimetrix Cytoscan HD (Quest Diagnostic, San Juan CA) identified an approximately 1 Mb deletion in chromosomal region 7q21.3. The reported coordinates of this abnormality were arr[hg19]7q21.3 (94,769,383-95,801,045). The chromosomal deletion included the genes PPP1R9A, PON1, PON3, PON2, ASB4, PDK4, DYNC1I1 and SLC25A13. All siblings and both parents were studied using the same technology. The proband's brother, individual II-1, was first evaluated by us at age 13 years. This patient had uncomplicated perinatal period. He did not have split hand/foot, but his nails were mildly hypoplastic. He had significant speech delay. Reportedly he was unable to make sentences until he was 3 years old. He had academic difficulties in school and now attends a special education class. On his latest psychology evaluation at age 15 he had a CGAS score of 55 similarly to his younger brother. He was also found to have a mood disorder with periods of depression. His ECHO exam was normal.
These three male siblings and their father were positive for the 7q21.3 deletion (see Fig. 1). The father did not have ectrodactyly and reportedly had mild learning disability while in school.
Consent for publishing the current report and the medical photography was obtained from the family.
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