PATIENT WITH A NOVEL STAG2 MATERNALLY INHERIETED MUTATION AND A NOVEL CELSR3 DENOVO VARTIANT
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Exome sequencing has been clinically used for the diagnosis of a wide variety of rare genetic conditions. Variants found with testing may provide insights regarding biological mechanisms explaining congenital anomalies. The STAG2 gene located at Xq25, encodes a core protein that, along with others make up the Cohesin protein complex. Genetic mutations were first linked to mild intellectual disability and characteristic facial features in 2012. Celsr3 is a part of a family of three cadherin EGF LAG seven-pass that encode atypical cadherins with variety of different neurological functions. CELSR3 has no disease process currently described with it. We present a male patient with unilateral microtia, hearing impairment and receptive language delay with a maternally inherited variant in STAG2 and a de novo variant in CELSR3.
Case Presentation
An 11-year-old male was brought for evaluation with history of developmental delay and right sided microtia. He was a full-term infant with no pregnancy complications. His right ear lobe was small and dysplastic with associated external auditory canal atresia and ipsilateral conductive hearing loss. He was followed by otolaryngology over time, and he was fit with a hearing aid. He was diagnosed with autism spectrum disorder at five years of age. He started walking at 15 months, and he was toilet trained at 5 years of age. He was reported to have exhibited cognitive decline and memory deficits between the ages of 4 and 5 years old. Currently, he is home schooled at the 5th grade level with special education for autism spectrum disorder. He writes at a 3rd grade level, and he reads at a 4th grade level. His math skills are at the 2nd grade level.
He has difficulties falling asleep with no concerns for frequent awakenings. He is described as very amicable and friendly with behavior described to correspond to an 8–9-year-old level. He is independent for his activities of daily living. However, he has a difficult time forming meaningful relationships with others, as he hyper focuses on details. Patient has a documented history of restrictive appetite and low weight. He is treated with Cyproheptadine for appetite stimulation and supplemental calories. He has alternating bouts of constipation and vomiting, for which he takes Polyethylene Glycol 3350 and Ondansetron 4 mg as needed.
He has a 19-year-old full biological brother with possible Asperger’s, and a maternal 23-year-old half-brother with a possible learning disability. He has a deceased 2nd cousin who was diagnosed with Duchenne muscular dystrophy, and his maternal grandmother is a known DMD carrier. His deceased maternal grandfather had a history of epilepsy.
On physical exam, his head circumference was 52.5 cm (42%ile). Facial features included right malar hypoplasia, right auricular dysplasia with normal left ear length 5.5 cm (25%ile). Three café-au-lait spots appear on his right upper extremity, and a large port wine covers most of the left lateral torso. Genitalia is at Tanner stage 2.
Diagnostic Workup
Standard Karyotype (550 G band) was 46, XY. Commercially available chromosome microarray (GeneDx; 2.67 million probes) was negative. Fragile X was hemizygous for 31 CGG repeats. Trio Exome sequencing showed a maternally inherited STAG2 (NM_001042749.2) variant of unknown significance denominated c.3584G>A p.(R1195H) and a de novo variant of uncertain significance, c.6 G>A p.(M2I) in CELSR3 (NM_001407.2).
Treatment and Management
No treatment available at this time.
Outcome and Follow-Up
Follow-up has not occured at this time.
Discussion
In this report, we describe an adolescent patient with a de novo variant in CELSR3 and a maternally inherited variant STAG2. The CELSR3 codes for a EGF LAG seven-pass cadherin that functions in a variety of roles [Goffinet and Tissir, 2017]. It has been shown to steer axons to their proper destination with the help of FZD3, help Purkinje cells reach maturation, and coordinate cerebellar postsynaptic plasticity through Wnt5a/cAMP and mGluR1/PKCa signaling [Chai et al., 2015; Zhou et al., 2021]. Five variants were identified in 2021 to have an unknown strength of association with febrile seizures and epilepsy with antecedent febrile seizures [Li et al., 2021]. It has also been well documented as being associated with poor prognosis of prostate cancer and hepatocarcinogenesis [Ouyang et al., 2020; Chen et al., 2021].
STAG2 codes for a cohesion subunit that is found on the Xq25 chromosome [Aoi et al., 2020]. STAG 2 is a core protein that combines with SMC1, SMC3, and RAD21 to form the Cohesion Protein Complex [Philippe et al., 2013]. Since being described, STAG2 variants have been described in Cornelia de Lange syndrome, α-thalassemia/mental retardation syndrome, Warsaw breakage syndrome, Chronic Atrial and Intestinal Dysrhythmia, that display common symptoms of limb malformations, inhibited growth, developmental delay, and behavioral phenotypes [Mullegama et al., 2017]. The first pathogenic germline was described in 2017 displaying reduce STAG2-SCC1 binding that resulted in characteristic syndromic mental retardation [Soardi et al., 2017]. Variants in STAG2, c.3097C>T, p.(Arg1033*) and c.2229G>A, p.(Trp743*), in 2019 were shown to display sex-distinct phenotypes [Aoi et al., 2019]. Finally, the first ever mosaic STAG 2 mutation producing developmental delay, microcephaly, and hemihypotrophy was described in 2022. However, all of these do not demonstrate the same phenotypical characteristics seen in this case.
Conclusion
This case presents a unique opportunity to expand the literature on two genes. Both variants are variants of uncertain significance. The STAG2 variant, c.3584G>A p.(R1195H), displayed an x-linked inheritance from the mother with hemizygosity. This variant can help to expand the phenotype qualities attributed to STAG2 related cohesinopathy. The CELSR3 variant, c.6 G>A p.(M21), on the other hand, has no disease currently described. This de novo variant means that there are almost endless possibilities on further avenues of exploration. With no correlated disease or phenotype, this variant can act as a bellwether for future research. Further research into both the STAG2 variant and especially the CELSR3 variant would provide useful insight into the full effects of these two mutations. Further research would increase the understanding of the similarities and differences between this mutation and the rest of the pathogenic mutations seen in the STAG2 gene. Further exploration would help to shape pathogenic, both physical and behavioral, phenotypes seen due CELSR3 variant.
Exome sequencing has been clinically used for the diagnosis of a wide variety of rare genetic conditions. Variants found with testing may provide insights regarding biological mechanisms explaining congenital anomalies. The STAG2 gene located at Xq25, encodes a core protein that, along with others make up the Cohesin protein complex. Genetic mutations were first linked to mild intellectual disability and characteristic facial features in 2012. Celsr3 is a part of a family of three cadherin EGF LAG seven-pass that encode atypical cadherins with variety of different neurological functions. CELSR3 has no disease process currently described with it. We present a male patient with unilateral microtia, hearing impairment and receptive language delay with a maternally inherited variant in STAG2 and a de novo variant in CELSR3.
Case Presentation
An 11-year-old male was brought for evaluation with history of developmental delay and right sided microtia. He was a full-term infant with no pregnancy complications. His right ear lobe was small and dysplastic with associated external auditory canal atresia and ipsilateral conductive hearing loss. He was followed by otolaryngology over time, and he was fit with a hearing aid. He was diagnosed with autism spectrum disorder at five years of age. He started walking at 15 months, and he was toilet trained at 5 years of age. He was reported to have exhibited cognitive decline and memory deficits between the ages of 4 and 5 years old. Currently, he is home schooled at the 5th grade level with special education for autism spectrum disorder. He writes at a 3rd grade level, and he reads at a 4th grade level. His math skills are at the 2nd grade level.
He has difficulties falling asleep with no concerns for frequent awakenings. He is described as very amicable and friendly with behavior described to correspond to an 8–9-year-old level. He is independent for his activities of daily living. However, he has a difficult time forming meaningful relationships with others, as he hyper focuses on details. Patient has a documented history of restrictive appetite and low weight. He is treated with Cyproheptadine for appetite stimulation and supplemental calories. He has alternating bouts of constipation and vomiting, for which he takes Polyethylene Glycol 3350 and Ondansetron 4 mg as needed.
He has a 19-year-old full biological brother with possible Asperger’s, and a maternal 23-year-old half-brother with a possible learning disability. He has a deceased 2nd cousin who was diagnosed with Duchenne muscular dystrophy, and his maternal grandmother is a known DMD carrier. His deceased maternal grandfather had a history of epilepsy.
On physical exam, his head circumference was 52.5 cm (42%ile). Facial features included right malar hypoplasia, right auricular dysplasia with normal left ear length 5.5 cm (25%ile). Three café-au-lait spots appear on his right upper extremity, and a large port wine covers most of the left lateral torso. Genitalia is at Tanner stage 2.
Diagnostic Workup
Standard Karyotype (550 G band) was 46, XY. Commercially available chromosome microarray (GeneDx; 2.67 million probes) was negative. Fragile X was hemizygous for 31 CGG repeats. Trio Exome sequencing showed a maternally inherited STAG2 (NM_001042749.2) variant of unknown significance denominated c.3584G>A p.(R1195H) and a de novo variant of uncertain significance, c.6 G>A p.(M2I) in CELSR3 (NM_001407.2).
Treatment and Management
No treatment available at this time.
Outcome and Follow-Up
Follow-up has not occured at this time.
Discussion
In this report, we describe an adolescent patient with a de novo variant in CELSR3 and a maternally inherited variant STAG2. The CELSR3 codes for a EGF LAG seven-pass cadherin that functions in a variety of roles [Goffinet and Tissir, 2017]. It has been shown to steer axons to their proper destination with the help of FZD3, help Purkinje cells reach maturation, and coordinate cerebellar postsynaptic plasticity through Wnt5a/cAMP and mGluR1/PKCa signaling [Chai et al., 2015; Zhou et al., 2021]. Five variants were identified in 2021 to have an unknown strength of association with febrile seizures and epilepsy with antecedent febrile seizures [Li et al., 2021]. It has also been well documented as being associated with poor prognosis of prostate cancer and hepatocarcinogenesis [Ouyang et al., 2020; Chen et al., 2021].
STAG2 codes for a cohesion subunit that is found on the Xq25 chromosome [Aoi et al., 2020]. STAG 2 is a core protein that combines with SMC1, SMC3, and RAD21 to form the Cohesion Protein Complex [Philippe et al., 2013]. Since being described, STAG2 variants have been described in Cornelia de Lange syndrome, α-thalassemia/mental retardation syndrome, Warsaw breakage syndrome, Chronic Atrial and Intestinal Dysrhythmia, that display common symptoms of limb malformations, inhibited growth, developmental delay, and behavioral phenotypes [Mullegama et al., 2017]. The first pathogenic germline was described in 2017 displaying reduce STAG2-SCC1 binding that resulted in characteristic syndromic mental retardation [Soardi et al., 2017]. Variants in STAG2, c.3097C>T, p.(Arg1033*) and c.2229G>A, p.(Trp743*), in 2019 were shown to display sex-distinct phenotypes [Aoi et al., 2019]. Finally, the first ever mosaic STAG 2 mutation producing developmental delay, microcephaly, and hemihypotrophy was described in 2022. However, all of these do not demonstrate the same phenotypical characteristics seen in this case.
Conclusion
This case presents a unique opportunity to expand the literature on two genes. Both variants are variants of uncertain significance. The STAG2 variant, c.3584G>A p.(R1195H), displayed an x-linked inheritance from the mother with hemizygosity. This variant can help to expand the phenotype qualities attributed to STAG2 related cohesinopathy. The CELSR3 variant, c.6 G>A p.(M21), on the other hand, has no disease currently described. This de novo variant means that there are almost endless possibilities on further avenues of exploration. With no correlated disease or phenotype, this variant can act as a bellwether for future research. Further research into both the STAG2 variant and especially the CELSR3 variant would provide useful insight into the full effects of these two mutations. Further research would increase the understanding of the similarities and differences between this mutation and the rest of the pathogenic mutations seen in the STAG2 gene. Further exploration would help to shape pathogenic, both physical and behavioral, phenotypes seen due CELSR3 variant.