Growth in individuals with SATB2‐associated syndrome Zarate, Yuri A.; Kannan, Amrit; Bosanko, Katherine A. ...
American journal of medical genetics. Part A,
October 2022, 2022-10-00, 20221001, Letnik:
188, Številka:
10
Journal Article
Recenzirano
SATB2‐associated syndrome (SAS) is an autosomal dominant multisystemic disorder caused by alterations in the SATB2 gene. In addition to a predominant neurodevelopmental phenotype, individuals with ...SAS often present with feeding difficulties and growth retardation that persist past infancy. In this study, we present growth and measurement data from 211 individuals (53.6% male, 46.4% female) with SAS due to different molecular mechanisms. To delineate growth in this population, we constructed SAS‐specific growth charts by sex from birth to 10 years of age. Smoothed SAS percentiles were superimposed with normative percentiles from WHO (birth to <24 months) and CDC (24 months to 10 years) growth charts. Individuals with SAS tend to display slower postnatal growth with 22.2% (32/144), 19.0% (26/137), and 21.6% having at least one weight, height, or weight‐for‐length /body mass index (BMI) measurement below −2 standard deviations, respectively. The SAS 50th centile BMI was consistently below the normative data 50th centile and negative mean Z‐scores were seen across almost all age groups analyzed for both genders. Individuals with chromosomal abnormalities displayed significantly lower weight for age Z‐score, height for age Z‐scores, occipitofrontal head circumference for age Z‐scores, and BMI for age Z‐scores compared to either missense or null variants.
SATB2‐associated syndrome in adolescents and adults Zarate, Yuri A.; Bosanko, Katherine A.; Caffrey, Aisling R.
American journal of medical genetics. Part A,
August 2021, 2021-08-00, 20210801, Letnik:
185, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The goal of this study was to investigate the medical, communication, activities of daily living (ADLs), and mental health concerns affecting adolescents and adults with SATB2‐associated syndrome ...(SAS). A comprehensive questionnaire was administered to the caregivers of 49 individuals 12 years or older with SAS (mean age was 19.4 years, range 12–37 years). For all individuals, medical records, including laboratory results, were reviewed. Most individuals required some degree of assistance for ADLs and none of the adults were able to live independently. Health status was qualified as excellent or very good in 61% of individuals. The most common medical problems were dental anomalies, with a significantly higher frequency of hypotonia and gastroesophageal reflux in younger individuals. Medical and surgical interventions were often required. Sixty‐nine percent (n = 33) of individuals spoke 10 or fewer words. Autism (41%), anxiety (37%), and attention deficit disorder (37%) were common with one third of individuals receiving medical treatments for these diagnoses. While medical and developmental problems in individuals with SAS were similar to those previously reported, many of these are persistent into adolescence and adulthood. This study provides better guidance for the challenges facing adults with SAS and their families.
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).
This study describes the molecular and clinical characterisation ...of 28 probands with NDD harbouring heterozygous
coding variants, occurring de novo for all those whose transmission could have been verified (26/28).
A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).
encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.
Our study establishes that de novo coding variants in
are involved in a novel monogenic form of NDD, highly similar to the recently reported
-related NDD.
SATB2‐Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous ...deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non‐ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = −2.3 to −1.1, p < 0.0001) and height (95% CI = −2.3 to −1.0, p < 0.0001) Z‐score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non‐ΔSAS individuals. We also present additional genotype–phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals ...with SATB2-associated syndrome.
We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible.
Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%).
Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual ...disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype.
Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2.
We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2.
We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
SATB2
-associated syndrome (SAS) is an autosomal dominant neurogenetic multisystemic disorder. We describe two individuals with global developmental delay and hypotonia who underwent an extensive ...evaluation to rule out an underlying mitochondrial disorder before their eventual diagnosis of SAS. Although the strict application of the clinical mitochondrial disease score only led to the designation of “possible” mitochondrial disorder for these two individuals, other documented abnormalities included nonspecific neuroimaging findings on magnetic resonance imaging and magnetic resonance spectroscopy, decreased complex I activity on muscle biopsy for patient 2, and variation in the size and relative proportion of types of muscle fibers in the muscle biopsies that were aligned with mitochondrial diseases. SAS should be in the differential diagnoses of mitochondrial disorders, and broad-spectrum diagnostic tests such as exome sequencing need to be considered early in the evaluation process of undiagnosed neurodevelopmental disorders.
A newborn presented to genetics with complex skeletal abnormalities, joint contractures, and bilateral corneal clouding with sclerocornea. The patient survived for 8 months before succumbing to ...respiratory failure. Exome sequencing revealed a compound heterozygous mutation in theB3GALT6gene. Mutations in this gene have been associated with both Ehlers- Danlos syndrome, progeroid type 2 and spondyloepimetaphyseal dysplasia with joint laxity type 1. These diagnoses encompass the skeletal and joint findings. Our patient expands the phenotype of these diagnoses, as anterior segment eye anomalies have not been described with either syndrome, and he is much more profoundly affected. Interestingly, our patient fits the description of a rare genetic disease referred to as Al-Gazali syndrome, for which the genetic cause is unknown.
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