Expanding the spectrum of microdeletion 4q21 syndrome: A partial phenotype with incomplete deletion of the minimal critical region and a new association with cleft palate and pierre robin sequence

Abstract

Microdeletion 4q21 syndrome has been described in about a dozen patients with deletions ranging from 3.2 to 15.1 MB with similar features including the distinctive facial characteristics of broad forehead, hypertelorism, and prominent front teeth, with severe growth delay, developmental delay, and neonatal hypotonia. A 1.37 MB minimal critical region has been described that accounts for this shared phenotype and includes five known genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1. We report on two new patients found through single nucleotide polymorphism (SNP) microarray testing that expand the reported phenotype. Patient 1 has a novel deletion of 2.0 MB, the smallest reported deletion, which involves only a partial deletion of the minimal critical region, including the genes HNRNPD, HNRPDL, and ENOPH1. She shares much of the typical phenotype including moderate developmental delay, unusual facial features, small hands and feet, but not any growth delay or neonatal hypotonia. This patient allows further genotype-phenotype correlation of the genes in the minimal critical region, and supports that heterozygous loss of PRKG2 leads to the growth delay. Patient 2 has a novel 3.4 MB deletion that includes the entire critical region, and has typical features, but also presented with cleft palate and Pierre Robin sequence, which have not been previously described. A gene reported to be associated with inherited cleft palate, SCD5, is in the deleted region in this patient, which suggests it may be playing a role in palate formation. Taken together, these patients allow for an expansion of the microdeletion 4q21 syndrome and provide candidate genes for particular features of the phenotype.

BMPR1Bmutation causes Pierre Robin sequence

“…The 4q21-qter is a previously defined CL/P (or PRS) locus. At least three studies suggested the presence of CL/P disease gene [25–27], and two studies indicated the presence of PRS disease gene [2, 28] located in the 4q21-qter interval.…”

4q21 microdeletion in a patient with epilepsy and brain malformations

“…These two genes have so far been the most promising candidates to account for the growth restriction and developmental delay, respectively. As previously noted, PRKG2‐ null mice have a dwarf phenotype, PRKG2 has been associated with idiopathic short stature in humans, and RASGEF1B is expressed in the central nervous system [Bonnet et al, ; Bhoj et al, ]. Furthermore, Patient 1 of Bhoj et al, who also has a partial 4q21 deletion sparing PRKG2 and RASGEF1B , has no growth restriction, no neonatal hypotonia, and relatively mild developmental delay with 8‐month‐old development at age 17 months [Bhoj et al, ; Patient 1].…”

“…As previously noted, PRKG2‐ null mice have a dwarf phenotype, PRKG2 has been associated with idiopathic short stature in humans, and RASGEF1B is expressed in the central nervous system [Bonnet et al, ; Bhoj et al, ]. Furthermore, Patient 1 of Bhoj et al, who also has a partial 4q21 deletion sparing PRKG2 and RASGEF1B , has no growth restriction, no neonatal hypotonia, and relatively mild developmental delay with 8‐month‐old development at age 17 months [Bhoj et al, ; Patient 1]. The presence in our patient of severe growth restriction, hypotonia, and developmental delay, despite preserved copy number of both PRKG2 and RASGEF1B , suggests that these genes may not be solely responsible for the growth restriction and neurological features in microdeletion 4q21 syndrome.…”

“…Additional phenotypic features in some patients include brain malformations [Fagan & Gill, 1989; Dobyns et al, ; Bonnet et al, ; Kulharya et al, ; Nowaczyk et al, ], liver tumors [Terada et al, ], and renal cysts associated with PKD2 loss [Velinov et al, ]. Recently, a patient was described having a microdeletion involving 3 of the 5 genes in the critical region, resulting in a modified phenotype with no growth delay, no hypotonia, and only moderate developmental delay [Bhoj et al, ]. We report on an additional patient with a partial deletion of the critical region who nevertheless has growth delay, hypotonia, and developmental delay, as well as epilepsy, brain malformations, and feeding difficulties contributing to growth delay.…”

Further defining the critical genes for the 4q21 microdeletion disorder

“…This is a non‐recurrent genomic disorder, presented with overlapping deletions of different size at 4q21 region. Currently, 48 cases (18 from literature [Bonnet et al, ; Dukes‐Rimsky et al, ; Tsang et al, ; Bhoj et al, ; Bartnik et al, ; Komlosi et al, ; Sakazume et al, ] and 30 cases from databases) with defined genomic coordinates have been reported and the majority of individuals with 4q21 deletion are characterized by neonatal hypotonia, intellectual disability, absent or delayed speech, marked progressive growth retardation, and variable degrees of brain malformation and facial dysmorphism.…”