A Rare Recurrent 4q25 Proximal Deletion Not Involving the PITX2 Gene: A Genomic Disorder Distinct from Axenfeld-Rieger Syndrome

Abstract

A de novo 1.2 Mb-4q25 proximal microdeletion encompassing the genes COL25A1 and ELOVL6 has been reported once in a 20-year-old woman. She had dysmorphic features and a complex behavioral phenotype, as described in table 1 [Verhoeven et al., 2013]. Through genotype-phenotype correlation, COL25A1 and EGF were proposed as candidate genes responsible for her unique phenotype [Verhoeven et al., 2013]. Prior to that publication, 4q25 microdeletion syndrome was mostly associated with Axenfeld-Rieger syndrome, with 95% of the affected patients having mutations or deletions involving the PITX2 gene or related upstream regulatory genes, often in a haploinsufficient manner [Amendt et al., 2000;Becker et al., 2003]. Here, we report on 2 additional patients (a child and his mother) having a smaller, but overlapping deletion characterized by a common behavioral and physical phenotype. The 3 patients combined suggest the existence of a novel 4q25 proximal deletion syndrome. Patients and Methods Clinical Case FindingsA 29-month-old Caucasian boy presented to our clinic with his 19-year-old mother. His medical history included birth via Cesarean section for fetal distress, eczema, and seasonal allergies. Key Words COL25A1 · Developmental delay · EGF · Hypotelorism · Hypotonia · Mandible asymmetry · Microdeletion 4q25Abstract Haploinsufficient microdeletions within chromosome 4q25 are often associated with Axenfeld-Rieger syndrome. A de novo 4q25 deletion, 675 kb proximal to PITX2 , has previously been reported once in an adult patient. The patient did not have Axenfeld-Rieger anomaly, but instead had intellectual disability and a complex behavioral phenotype with withdrawn, stereotypic, and ritualistic behavior. Array comparative genome hybridization demonstrated a smaller, overlapping 4q25 deletion in a 2-year-old patient and his mother, both having significant phenotypic overlap with the initially reported patient. All 3 patients have distinct facial features (including mild hypotelorism and subtle mandibular asymmetry), developmental delay, and complex behavioral difficulties. A genotype-phenotype correlation narrows the shared phenotype to a common COL25A1 gene aberration and proposes that the concurrent EGF gene loss has a significant impact on the phenotypic severity. Overall, our patients provide data to support the existence of a novel 4q25 proximal deletion syndrome.

A proximal 300kb deletion further defining critical regions in 4q25 syndrome

“…Three patients have previously been reported in two case studies which describe a novel proximal 4q25 deletion syndrome, not involving the PITX3 gene (Heithaus et al ., 2016; Verhoven et al ., 2013). All three reported individuals had larger deletions than that of our patients but these included loss of part of COL25A1 and complete loss of SEC24B.…”

4q25 Microdeletion with Axenfeld-Rieger Syndrome and Developmental Delay

“…Recent advances in microarray analysis have led to the identifcation of many other causative genes and regions. With the exception of a few reports on 4q25 microdeletion that did not include the PITX2 gene region [2,3], 4q25 microdeletion is mainly a case of Axenfeld-Rieger syndrome (ARS) caused by abnormalities in the PITX2 gene (MIM# 601542) [4]. PITX2 encodes paired-like homeodomain transcription factor 2, which is involved in the development of eyes, teeth, and abdominal organs [5].…”