Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome

Abstract

Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/ velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin's deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk.

Clinical Features and Follow-Up in Patients with 22q11.2 Deletion Syndrome

“…This could be explained by genetic predisposition to deletions in some families or the presence of germline mosaicism, although independent de novo events in the same family cannot be excluded. [21][22][23] Neonatal hypocalcemia caused by hypoparathyroidism is one of the cardinal symptoms of 22q11DS. In our series, it was reported in only 43% of cases but may have been underestimated because blood calcium levels were tested only in symptomatic patients.…”

Velo-cardio-facial syndrome

“…The unique arrangement of 22q11.2 that makes it a hot spot for rearrangement has been traced as an evolutionary change in the structure of human DNA as described in a 2003 study by Babcock and colleagues from the Albert Einstein College of Medicine. The 'hot' nature of the region is further illustrated by a report of first cousins who both had de-novo deletions at 22q11.2 [77].…”

Disrupted ERK Signaling during Cortical Development Leads to Abnormal Progenitor Proliferation, Neuronal and Network Excitability and Behavior, Modeling Human Neuro-Cardio-Facial-Cutaneous and Related Syndromes

“…Chromosomal duplications/ deletions of 16p11.2, which includes the MAPK3 gene encoding ERK1, are the most common genetic cause of autism (Campbell et al, 2008;Fernandez et al, 2010). Moreover, Saitta and others identified a cohort of patients with a 1 Mb microdeletion on chromosome 22, which encompasses the MAPK1 (ERK2) gene (Saitta et al, 2004). These individuals exhibit neurodevelopmental deficits indistinguishable from classical DiGeorge syndrome.…”