Phenotypic Variability Associated with a Large Recurrent 1q21.1 Microduplication in a Three-Generation Family

Abstract

Recurrent copy number variants of the q21.1 region of chromosome 1 have been associated with variable clinical features, including developmental delay, mild to moderate intellectual disability, psychiatric and behavioral problems, congenital heart malformations, and craniofacial abnormalities. A subset of individuals is clinically unaffected. We describe a unique 3-generation family with a large recurrent 1q21.1 microduplication (BP2-BP4). Our observations underline the incomplete penetrance and phenotypic variability of this rearrangement. We also confirm the association with congenital heart malformations, chronic depression, and anxiety. Furthermore, we report a broader range of dysmorphic features. The extreme phenotypic heterogeneity observed in this family suggests that additional factors modify the clinical phenotype.

Genetic Evaluation and Use of Chromosome Microarray in Patients with Isolated Heart Defects: Benefits and Challenges of a New Model in Cardiovascular Care

“…Early involvement of the clinical genetics team provides the opportunity for earlier recognition of syndromic conditions, which can result in more comprehensive medical interventions and therapies as well as improved prognosis, compared to those patients who receive a syndromic diagnosis later in life. There is also increasing recognition that many delineated syndromes have broader phenotypic variability than previously thought ( 34 , 35 , 48 ). Many syndromes may not be recognized earlier in life due to absence of the “classic” defining features ( 49 ).…”

Variation of DNA copies number in etiology of congenital heart defects

“…5 из 7 сибсов 3 поколения были носителями микродупликации. Большая часть членов семьи имела специфические лицевые черты с их усилением в каждом поколении и неврологические заболевания [39]. Этот семейный случай демонстрирует неполную пенетрантность CNV с усилением проявлений в каждом последующем поколении.…”

Prenatal Diagnosis of Recurrent Distal 1q21.1 Duplication in Three Fetuses With Ultrasound Anomalies

“…Individuals with 1q21.1 duplication (OMIM 612475) are reportedly associated with a spectrum of macrocephaly, autism spectrum disorder, dysmorphic features, and congenital anomalies. In recent years, the application of CMA allows for more patients with 1q21.1 duplication to be revealed ( Brunetti-Pierri et al, 2008 ; Mefford et al, 2008 ; Rosenfeld et al, 2012 ; Soemedi et al, 2012 ; Dolcetti et al, 2013 ; Verhagen et al, 2015 ; Bernier et al, 2016 ; Buse et al, 2017 ; Wang et al, 2017 ). Highly diverse inter- and intrafamilial outcomes were observed among patients harboring 1q21.1 duplication, from almost normal to severely affected ( Brunetti-Pierri et al, 2008 ; Mefford et al, 2008 ; Dolcetti et al, 2013 ; Buse et al, 2017 ).…”

“…Chromosomal region 1q21.1 is structurally complex with many SDs that make it prone to NAHR ( Sharp et al, 2005 ; Mefford et al, 2008 ). Some scholars believed that the chromosome 1q21.1 region can be subdivided into two distinctive regions ( Rosenfeld et al, 2012 ; Verhagen et al, 2015 ; Wang et al, 2017 ). The proximal region, which is flanked by SDs, extends recurrent BPs from BP2 and BP3 (spans about 200 Kb), and the distal region extends from BP3 to BP4 (spans about 1.35 Mb).…”

“…Up to now, only two prenatal cases with 1q21.1 duplication were reported in literature ( Liao et al, 2012 ; Verhagen et al, 2015 ). To provide a better understanding of this submicroscopic imbalance in prenatal diagnosis, we present our study on prenatal diagnosis of recurrent distal 1q21.1 duplication in three fetuses with ultrasound anomalies.…”