Duplication Xp11.22‐p14 in females: Does X‐inactivation help in assessing their significance?

Abstract

In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic.

Unusual X‐chromosome inactivation pattern in patients with Xp11.23‐p11.22 duplication: Report and review

“…However, female carriers usually present skewed inactivation pattern in favor of the duplicated chromosome, resulting in functional disomy of the duplicated segment and leading to a severe phenotype [Evers et al, ]. This unexpected X‐chromosome inactivation pattern was also observed in our patient and we showed that it cannot be attributed to a deleterious variant in the normal X‐chromosome, since the patient's mother has a random X‐chromosome inactivation pattern and normal phenotype.…”

“…This duplication occurs with higher incidence and a larger size in females, ranging from 0.3 to 4.4 Mb in males and from 4.5 to 12.3 Mb in females [Holden et al, ; Nizon et al, ].Consistent with our results, in all de novo cases in which the parental origin was verified, the duplication originated from the paternal X‐chromosome. On the other hand, all inherited duplications had a maternal origin, giving rise to familial cases [Evers et al, ]. Specific factors might be associated with instability in spermatogenesis giving rise to this duplicated chromosome, explaining why most patients are females [Holden et al, ].…”

“…This unexpected X‐chromosome inactivation pattern was also observed in our patient and we showed that it cannot be attributed to a deleterious variant in the normal X‐chromosome, since the patient's mother has a random X‐chromosome inactivation pattern and normal phenotype. On the other hand, it has been suggested that Xp11.23‐p11.22 gain of genetic material can play a role in the mechanism of positive selection of cells with the altered X‐chromosome being active during development [Evers et al, ].…”

A De Novo Xp11.23 Duplication in a Girl with a Severe Phenotype: Expanding the Clinical Spectrum

“…The seizures of both twins were well controlled by therapy with sodium valproate and no further seizures occurred. 16 Our patient developed medically refractory epilepsy. She experienced one or two focal and/or generalized tonicclonic seizures per month, usually associated with infections with fever.…”

“…They also reported a female with febrile seizures. 16 Our patient had recurrent hospital admissions because of pneumonia and fever. Serum IgG, IgA, and IgM levels and lymphocyte count were within normal range.…”