Abnormalities in amniotic fluid chip analysis, with microduplication and microdeletion in the p13.3 region of chromosome 16?
Hello Doctor, I am a 30-year-old first-time mother who is 20 weeks pregnant.
I have Graves' disease, which is well-controlled with medication.
I have had intermittent mild microcytic anemia in the past, and my doctor has suspected either thalassemia or iron deficiency anemia.
After taking iron supplements for a period, my hemoglobin and red blood cell size have remained within normal ranges.
My husband is 34 years old and has no significant medical history.
My aunt's child (my father's cousin) is suspected to have a congenital anomaly (such as anal atresia, clubfoot, or hand joint abnormalities), and my husband's aunt's daughter (his cousin) has an intellectual disability.
We underwent amniocentesis and amniotic fluid chromosomal analysis at 17 weeks of pregnancy.
The amniocentesis chromosomal report was normal (46XX), but the amniotic fluid chromosomal analysis revealed a microdeletion of 0.0006 Mb (633 bp) and a microduplication of 0.34 Mb in the p13.3 region of chromosome 16.
The deletion in the HBA gene in the 16p13.3 region was identified as a carrier of alpha-thalassemia through gap PCR and gel electrophoresis.
However, the duplicated region includes genes such as CREBBP, ADCY9, and LOC102724927, and no abnormalities were detected in the specific single-gene disease common pathogenic site testing.
Further analysis using MLPA-P313-A1 confirmed the duplication of CREBBP exons 1-16.
The ISCN nomenclature indicates arr〔GRCh37〕(X)x2,16p13.3(225,052_225,684)x1, 16p13.3(3,817,791_4,153,173)x3.
Since Rubinstein-Taybi syndrome (RSTS) is associated with CREBBP gene mutations or deletions, we researched 16p13.3 duplication syndrome and found that the clinical features of both may be similar and exhibit incomplete penetrance.
Clinical manifestations of 16p13.3 microduplication often affect the HAT region of CREBBP, specifically exons 17-31, and reports on CREBBP exon 1-16 duplication are extremely rare.
Data indicates that CREBBP exon 1-16 mainly contains the KIX (CREB binding region) and zinc finger domains, while the significance of other exons seems unclear.
However, we found a single report of a heterozygous duplication of CREBBP exon 1, which also presented typical RSTS features clinically.
My husband and I have undergone genetic testing and are awaiting the results.
I would like to ask if you have encountered similar cases of CREBBP exon 1-16 microduplication? What are the potential clinical manifestations of such genetic abnormalities in the fetus? We deeply cherish this hard-won child, and we hope for your guidance.
Thank you!
Luo, 30~39 year old female. Ask Date: 2021/08/09
Dr. Jian Yingxiu reply Rare Disease
Hello: Anticipating new life yet encountering such uncertainty can indeed be unsettling.
It seems you have already gathered all the information, but due to incomplete penetrance, even if one parent has similar chromosomal variations, there is still a chance that the baby may experience conditions similar to RSTS or related learning difficulties.
I encourage you and your spouse to thoroughly discuss your future plans, as a comprehensive discussion is essential to find the best answers for your baby.
Reply Date: 2021/08/09
More Info
The concerns surrounding the 16p13.3 microduplication and its implications for fetal health are indeed complex and warrant careful consideration. The 16p13.3 region is known to harbor several genes, including the CREBBP gene, which is associated with Rubinstein-Taybi syndrome (RSTS). This syndrome is characterized by distinct physical features, intellectual disability, and growth delays, among other symptoms. However, it is important to note that the clinical manifestations of genetic abnormalities can vary significantly among individuals, even when they share the same genetic alteration.
In your case, the report indicates a microdeletion of 0.0006Mb and a microduplication of 0.34Mb in the 16p13.3 region. The presence of the CREBBP gene duplication, particularly involving exons 1-16, raises questions about potential clinical outcomes. While there are documented cases of CREBBP mutations leading to RSTS, the specific implications of a duplication in this region are less well understood. The incomplete penetrance associated with this microduplication means that not all individuals with the same genetic alteration will exhibit symptoms, which adds another layer of uncertainty.
The external factors, such as your family history of congenital anomalies and intellectual disabilities, may also play a role in the overall risk assessment for your child. However, it is crucial to remember that genetic conditions can arise sporadically and are not solely determined by family history. The fact that your amniocentesis results showed normal chromosomal analysis (46XX) is reassuring, but the presence of the microduplication still necessitates further evaluation.
Regarding the potential clinical features associated with CREBBP exon 1-16 microduplication, there is limited literature available. The unique nature of your findings suggests that this may be an area of ongoing research, and it is essential to consult with a genetic counselor or a specialist in genetics who can provide more tailored insights based on the latest research and clinical guidelines. They can help interpret the significance of the microduplication in the context of your family history and the specific genetic findings.
As for the management of your pregnancy and the health of your child, it is advisable to maintain regular prenatal care and follow up with your healthcare provider regarding any additional screening or monitoring that may be warranted. Genetic counseling will also be beneficial in understanding the implications of the findings and discussing potential outcomes, including the possibility of developmental assessments and early intervention services if needed.
In summary, while the presence of a microduplication in the 16p13.3 region raises valid concerns, the clinical implications can vary widely. Engaging with healthcare professionals who specialize in genetics will provide you with the most accurate and relevant information to guide your decisions moving forward. Your proactive approach to understanding these complexities is commendable, and it is essential to continue seeking support and information as you navigate this journey.
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