ABSTRACT Hemizygosity for a pathogenic loss‐of‐function FLNA ( Filamin A ) variant typically leads to male lethality in utero or early childhood. A small number of surviving males with loss of function variants have been reported, but these show either mosaicism for a variant at the genomic DNA level or are hypomorphic alleles. We present a surviving male proband with periventricular nodular heterotopia (PVNH) who is hemizygous at the genomic DNA level for a FLNA splice variant. In addition, we present a second surviving male proband who is also hemizygous at the genomic DNA level for a different FLNA splice variant, but whose RNA transcripts show opposite functional and hence phenotypic outcomes. RNA studies have shown that both patients have a complex pattern with multiple transcripts. In the patient with PVNH, the splice variant results in two abnormal transcripts: one frameshift variant arising from intron retention, and a three amino acid insertion assumed to provide enough functional compensation to be compatible with life. In the patient with frontometaphyseal dysplasia (FMD), leaky splicing results in a mixture of wild‐type transcripts (~70%), transcripts with a loss‐of‐function out‐of‐frame insertion due to an intronic cryptic acceptor site (~25%), and ~5% of transcripts with an in‐frame deletion due to the use of an exonic cryptic acceptor site, leading to a mixture of loss‐of‐function, gain‐of‐function, and wild‐type transcripts at the cellular level. In this latter patient, it is proposed that it is the small proportion of gain‐of‐function transcripts that solely impacted on the patient phenotype. This is the first reported case of male survivorship in a PVNH proband where differential splicing of an intronic variant produces two abnormal RNA transcripts but no wild‐type RNA transcripts. In the proband with FMD, RNA results showed both gain‐ and loss‐of‐function transcripts, with the least abundant transcript contributing solely to the phenotype. These cases highlight both the importance of the detection of FLNA intronic variants and the necessity of RNA studies to further increase our understanding of the complexity of FLNA genotype/phenotype correlations.
ABSTRACT This cross‐sectional study investigated associations between screening positive for attention‐deficit/hyperactivity disorder (ADHD) and quality of life (QoL), as well as real‐life functioning, in 235 adults with neurofibromatosis 1 (NF1). Self‐reported data included ADHD symptoms (Adult Self‐Report ADHD Scale v1.1), QoL (PedsQL NF1 Module), partner status, and need for daily support, supplemented by registry data on education and employment. Adults screening positive for ADHD (14%) had a mean QoL score that was 16.0 points lower (95% confidence interval [CI]: −20.2 to −11.7) than that of adults who screened negative. Each 1‐point increase in inattention or hyperactivity/impulsivity score was associated with a mean decrease in QoL of 0.9 (95% CI: −1.1, −0.7) and 0.5 (95% CI: −0.7, −0.3). Screening positive for ADHD was associated with lower odds of having a medium/long education (odds ratio [OR]: 0.24, 95% CI: 0.10–0.56) and being employed (OR: 0.20, 95% CI: 0.10–0.50), but not with having a partner (OR: 0.73, 95% CI: 0.34–1.56). ADHD was also associated with a greater need for daily support, including physical (OR: 8.7, 95% CI: 3.6–21.1), family‐related (OR: 5.7, 95% CI: 2.4–13.3), and psychological (OR: 5.0, 95% CI: 2.2–11.3) support. These results support assessment of ADHD symptoms in adults with NF1 to facilitate timely treatment and care.
ABSTRACT Studying Mendelian neurodevelopmental disorders (NDDs) from a bottom‐up perspective, in which neurocognitive functioning is conceptualized as a mediator between genotype and behavioral phenotype, may facilitate early identification of syndrome‐specific vulnerabilities. This study characterizes the neurocognitive phenotype and adaptive functioning of children with Coffin‐Siris syndrome (CSS), a rare Mendelian NDD with unknown effects on brain development. Thirty‐five children with CSS (Mage = 9.74 years, SD = 4.22) underwent performance‐based assessment of global cognition, receptive and expressive language, and visuomotor integration. Parents completed standardized questionnaires assessing adaptive functioning. The predictive value of age and cognitive performance for adaptive outcomes was explored. Children with CSS showed marked developmental delays across global cognition and domain‐specific skills. Receptive language emerged as a relative strength, whereas expressive language and visuomotor integration were prominent vulnerabilities. Adaptive functioning was broadly impaired, particularly in communication, self‐regulation, being part of the community, and daily functioning. Older children showed larger divergence from age‐expected norms, consistent with a growing‐into‐deficit pattern. Receptive language, expressive language, and visuomotor integration each uniquely contributed to adaptive behavior, independent of global cognitive level. These findings underscore the importance of individualized neurocognitive assessment to guide targeted interventions improving daily functioning in children with CSS.
ABSTRACT Primary immunodeficiency disorders may present with gastrointestinal inflammation resembling inflammatory bowel disease (IBD), particularly in patients with pediatric or very‐early‐onset disease. We report a 24‐year‐old male with lifelong immune dysregulation and early‐onset IBD who was ultimately found to carry a hemizygous intronic IL2RG variant (c.270‐14C>G). Despite extensive infectious complications, lymphoproliferative disease, and chronic lung pathology, his Crohn's‐like intestinal inflammation had been managed successfully with azathioprine. Genome sequencing followed by RNA analysis demonstrated that the IL2RG variant introduced a cryptic splice acceptor site, causing aberrant splicing, intron retention, and a premature stop codon, confirming a diagnosis of atypical or hypomorphic X‐linked severe combined immunodeficiency (X‐SCID). This case expands the phenotypic spectrum of X‐SCID to include chronic IBD‐like enterocolitis and underscores the diagnostic utility of comprehensive genomic and transcriptomic testing in patients with complex, unexplained immune and gastrointestinal disease. Recognition of atypical presentations of X‐SCID has implications for surveillance, prognosis, and consideration of definitive therapies.
