Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size

Halder, Ashutosh; Jain, Manish; Chaudhary, Isha; Varma, Binuja

doi:10.1186/1755-8166-5-13

Cited by 39 publications

(28 citation statements)

References 34 publications

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“…However, Rauch et al (2005) demonstrated a correlation between deletion characteristics and phenotypic expression by assessment of individuals with typical and atypical 22q11.2 deletions, showing that atypical CHD and mild dysmorphism are recognizable feature of atypical distal deletions [20]. Recently, a case-report of monozygotic twins differing in their deletion size and clinical expression was published, indicating a possible role of deletion characteristics for the phenotype [31]. …”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlation in 22q11.2 deletion syndrome

et al. 2012

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BackgroundThe 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.MethodsMolecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.ResultsDeletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.ConclusionsMLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

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Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlation in 22q11.2 deletion syndrome

et al. 2012

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“…22q11DS is characterized by variable expressivity, and phenotypic discordance between monozygotic twins (McDonald-McGinn, 2001; Halder, Jain, Chaudhary, & Varma, 2012). In light of the variable expressivity, it is important to identify clinical correlations between cardinal features.…”

Section: Introductionmentioning

confidence: 99%

Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome

Rayannavar

Katz

Crowley

et al. 2018

American J of Med Genetics Pt A

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Hypocalcemia is one of the cardinal features of the chromosome 22q11.2 deletion syndrome (22q11.2DS), the most common cause of DiGeorge syndrome. Hypocalcemia and other features of 22q11.2DS including congenital heart disease (CHD) are primarily ascribed to problems with morphogenesis and function of the pharyngeal arch system derivatives including the parathyroid glands, the aortic arch, and the cardiac outflow tract. In light of the aforementioned embryology, we hypothesized that hypocalcemia would be identified more frequently in those patients with 22q11.2DS and CHD. We conducted a retrospective IRB approved chart review on 1,300 subjects with 22q11.2DS evaluated at the Children’s Hospital of Philadelphia. χ2 test was used to evaluate the statistical significance of differences in hypocalcemia between the two groups. Eight hundred fifty-two patients had calcium levels available for review. Of these, 466 (54.69%) had a history of hypocalcemia and 550 (64.55%) had CHD. Of those with CHD, 343 (62.36%) had a history of hypocalcemia, and of those without CHD, only 123 (40.73%) had a history of hypocalcemia. Thus, the frequency of diagnosed hypocalcemia was greater in patients with 22q11.2DS and CHD as compared to those without CHD (p < .001). We also analyzed age of onset of hypocalcemia and found that 66.47% of CHD/hypocalcemia group had neonatal/infantile hypocalcemia versus 43.09% in the non-CHD/hypocalcemia group. In our large cohort of patients with 22q11.2DS, the prevalence of diagnosed hypocalcemia is elevated among patients with CHD, in whom it is more likely to be diagnosed during the neonatal/infancy period.

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“…Recently, a high resolution single nucleotide polymorphism (SNP)-array allowed for the detection of copy number variants (CNVs) as well as SNPs. Halder et al (12) reported a case in which twins carrying the 22q11.2DS microdeletion had discordant phenotypes with a different sized genetic deletion. Another technique, exome sequencing, offers an efficient and affordable method to investigate the genetic factors involved in human diseases (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

et al. 2015

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Abstract. Smith-Magenis syndrome (SMS) is a rare condition with multiple congenital malformations caused by the haploinsufficiency of RAI1 (deletion or mutation of RAI1). However, the correlation between genotype and phenotype is not well understood. The present study describes the prenatal diagnosis of monozygotic twins with a 17p11.2 deletion, which is indicative of SMS, who presented with discordant phenotypes and uteroplacental insufficiency. A high-resolution genome-wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in the 17p11.2 chromosome region. Accurate breakpoints of the deletion in these patients were used to identify correlations between SMS and the concomitant phenotypes, particularly uteroplacental insufficiency, which has rarely been investigated in SMS. In addition, no exonic mutations were identified in or affected known disease-associated loci that could explain the congenital anomalies, according to a model that accounts for the possibility of incomplete penetrance. Furthermore, a novel benign copy number variation (a duplication of 195 kb at 13q12.13) was identified but was unlikely to be clinically significant in the discordant phenotypes of the twins. The present study showed that multiple interacting genetic and environmental factors are involved in determining the variance of the SMS phenotype.

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Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size

Cited by 39 publications

References 34 publications

Genotype-phenotype correlation in 22q11.2 deletion syndrome

Genotype-phenotype correlation in 22q11.2 deletion syndrome

Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome

Smith‑Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency

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