Case Report: genotype–phenotype correlations in FLNA mutations: insights from a case of multisystem dysfunction

Background: Filamin A (FLNA) mutations are associated with the development of numerous diseases and disorders. Although recent studies have shed light on genotype–phenotype relationships, the evidence remains fragmented.

Case presentation: Herein, we report the case of a male infant with an FLNA nonsense mutation (c.5265C>G; p.Tyr1755*) identified through trio whole-exome sequencing. The patient exhibited multisystem dysfunction, including periventricular nodular heterotopia, congenital heart disease (perimembranous ventricular septal defect), congenital short bowel syndrome, lung disease, and fatal sepsis. We analyzed this case along with a systematic review of 62 cases of male patients with FLNA mutations to explore genotype–phenotype relationships. Results: Following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines, the variant was classified as likely pathogenic (PVS1, PM2, and PP3). Segregation analysis confirmed maternal inheritance. Standard genetic testing (karyotype and CGH-array) results were unremarkable.

Conclusion: This case expands the phenotypic spectrum of FLNA deficiency, linking a nonsense mutation to a severe clinical course with fatal complications such as necrotizing enterocolitis and sepsis, highlighting the need for vigilant multi-organ monitoring.

1 Introduction

Filamin A (FLNA), located at Xq28 on the X chromosome, encodes an actin-binding protein essential for cell adhesion, migration, and mechanotransduction. Structurally, FLNA spans approximately 48 kb and consists of 48 exons, encoding a large homodimeric protein with key domains such as an N-terminal actin-binding domain and 24 immunoglobulin-like repeats. The C-terminal region facilitates dimerization, forming a flexible V-shaped molecule that cross-links actin filaments into dynamic networks and serves as a scaffold for numerous signaling proteins (Sheen et al., 2005). Pathogenic FLNA variants are associated with the development of numerous conditions, including periventricular nodular heterotopia (PNH), congenital heart disease (CHD), and Ehlers-Danlos syndrome-like disorders (Reinstein et al., 2013). However, the genotype–phenotype correlations remain unclear. Gain-of-function mutations can cause syndromic diseases, while loss-of-function mutations lead to non-syndromic diseases (De Wit et al., 2011a). FLNA-deficient patients are often overlooked or misdiagnosed, highlighting the need to redefine the phenotypic diversity linked to FLNA deficiency (Oda et al., 2016). Herein, we report the case of a full-term male infant with a novel FLNA mutation and multisystemic dysfunctions, broadening the known phenotypic spectrum of FLNA-related disorders.

2 Case presentation

A 2-month-old boy was admitted to the pediatric intensive care unit (PICU) with a fever (39 °C), tachypnea with chest retractions, oxygen saturation of 80% in room air, and tachycardia (180 bpm). The boy showed mild acrocyanosis, diminished subcutaneous fat level (skinfold thickness <3rd percentile), abdominal distention, and a 2–3/6 systolic murmur. The patient had an unusual medical history (Figure 1), but clinical examination revealed no obvious dysmorphism. He was delivered via planned Caesarean section at 38 weeks and 3 days of gestation owing to a fetal ventricular septal defect (VSD) and suspected PNH noted on magnetic resonance imaging (MRI). Prenatal genetic testing was prompted by maternal cardiac ultrasound findings of an asymptomatic ventricular septal aneurysm, paternal abdominal hypopigmented patches, and fetal ultrasound indicating CHD and a widened posterior cranial fossa. A multidisciplinary consultation at 30 weeks of gestation led to trio whole-exome sequencing, which revealed a hemizygous nonsense mutation in FLNA (c.5265C>G; p.Y1755*) in the proband. Segregation analysis confirmed that the variant was inherited from his mother (a heterozygous carrier). The proband is the first child of non-consanguineous parents with no family history of FLNA-related disorders, which was confirmed using segregation analysis (Figure 2). Karyotype and CGH-array results were normal. At birth, the patient exhibited appropriate anthropometry (weight 2,850 g, height 49 cm, and head circumference 34 cm) and good cardiorespiratory adaptation (Apgar scores 9/10). However, he developed respiratory distress syndrome (Figure 3A) requiring mechanical ventilation, surfactant therapy, and neonatal intensive care unit admission. Subsequent examinations revealed a perimembranous VSD (Figure 3B), a left subependymal cystic lesion, thrombocytopenia (platelet nadir 42 × 10⁹/L), and pulmonary emphysema. After 1 month of hospitalization, the patient was discharged with a weight of 3,010 g. Cardiac and neurodevelopmental follow-ups were suggested owing to the high risk of epilepsy and intellectual disability associated with the FLNA mutation. Although neurological examination and developmental assessment results were normal, given the high-risk history of the patient, a brain MRI was performed. The MRI indicated bilateral PNH alongside the mega cisterna magna (Figures 3C,D). Additionally, electroencephalography demonstrated frequent centroparietotemporal spikes and spike–wave discharges (sleep-activated), and the chest X-ray showed pulmonary interstitial changes (Figure 3E). Laboratory tests revealed elevated transaminase levels (peak alanine aminotransferase level, 135 U/L; aspartate aminotransferase level, 314 U/L), myocardial damage (peak troponin level, 109 ng/L; B-type natriuretic peptide level, 754.16 pg/mL), and coagulation dysfunction (low-grade coagulopathy). Further metagenomic next-generation sequencing of peripheral blood revealed the presence of Klebsiella pneumoniae, Enterococcus faecium, and human mastadenovirus B. Consequently, the patient required mechanical ventilatory support and targeted antimicrobial therapy throughout the 21-day hospitalization period. The patient was readmitted to the PICU within 4 days of discharge owing to the recurrence of fever, along with reduced oral intake, drowsiness with impaired alertness, and decreased urine output (<1 mL/kg/h). Isolation of a carbapenemase-producing Enterobacter cloacae complex from a sputum culture (≥10⁵ CFU/mL) demonstrated resistance to meropenem (minimum inhibitory concentration [MIC] >8 mg/L) and imipenem (MIC >4 mg/L), along with recurrent episodes of metabolic acidosis (lowest PH: 7.094) and associated electrolyte derangements (particularly hypokalemia and hyponatremia). Despite administering targeted treatment, the patient subsequently developed vomiting, abdominal distension, and hematochezia, accompanied by diminished bowel sounds on auscultation and a progressive increase in C-reactive protein level (from 34.4 to 79.2 mg/L in 48 h). Abdominal computed tomography revealed extensive pneumatosis coli along with bowel wall edema suggestive of necrotizing enterocolitis (NEC) (Figures 3F,G). Owing to persistent symptoms that were unresponsive to maximal medical therapy, the patient underwent laparoscopic intervention. It revealed a markedly dilated small bowel measuring approximately 90 cm in length and 3 cm in diameter, with gradual luminal narrowing beginning from 60 cm distal to the ligament of Treitz (reduced to a diameter of 2 cm). The caecum was mobile and positioned normally, whereas the colonic luminal diameter remained consistent at 1.5 cm. Biopsy of the ileum was performed along with a Santulli ileostomy. Normal ganglion cells were observed, with areas of mucosal erosion, necrosis, and suppurative inflammation. The prolonged and complicated clinical course required comprehensive support, including parenteral nutrition comprising proteins, glucose, fats, and essential vitamins, following consultations with gastroenterologists and nutritionists. However, the patient ultimately developed fatal sepsis, malignant arrhythmia, and multi-organ failure following multiple unsuccessful attempts at extubation.

Figure 1

Figure 1. Timeline depicting case progression, cultures/imaging/antibiotic treatment, and mNGS (dates are in the mm/dd/yyyy format). Abbreviations: CPC, cisterna posterior cranial; AC, abdominal circumference; GA, gestational age; sPNH (L), suspected periventricular nodular heterotopia (left); WES, whole-exome sequencing; ARDS, acute respiratory distress syndrome; VSD, ventricular septal defect; MV, mechanical ventilation; CPAP, continuous positive airway pressure; F/U, follow-up; PNH, periventricular nodular heterotopia; TNT, troponin T; BNP, B-type natriuretic peptide; WBC+, pus cells present; FOBT+, fecal occult blood positive; CRE, carbapenem-resistant Enterobacteriaceae; NEC, necrotizing enterocolitis; TPN, total parenteral nutrition.

Figure 2

Figure 2. Pedigree of the proband’s family. A heterozygous nonsense mutation (c.5265C>G) in the FLNA gene was identified in the proband’s mother (I-2), while the father (I-1) was normal.

Figure 3

Figure 3. Imaging findings of the patient. (A) Chest X-ray demonstrating bilateral diffuse decreased lung lucency; (B) transthoracic echocardiography demonstrating perimembranous VSD (white arrow); (C,D) cerebral MR imaging demonstrating bilateral PNH (blue arrows) and a large mega cisterna magna; (E) chest X-ray showing interstitial changes; (F,G) abdominal CT demonstrating extensive hepatic portal venous gas (orange arrow) and intestinal wall thickening (yellow arrow). Abbreviations: VSD, ventricular septal defect; PNH, periventricular nodular heterotopia.

3 Materials and methods

3.1 Ethical consideration and data collection

This study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Review Committee of West China Second University Hospital, Sichuan University (Approval Code: KJ-2017-046-4). Clinical data were collected from the medical records of the patient.

3.2 Genetic and bioinformatic analyses

Genetic analysis was performed using capture-based next-generation sequencing with the reference transcript NM_001456.4 (FLNA). Specifically, trio whole-exome sequencing (WES) was performed on genomic DNA extracted from amniotic fluid (fetus) and peripheral blood (parents). The mean depth of coverage for the exome was >100×, with >98% of the target regions covered at least 20×. The novel status of the FLNA c.5265C>G variant, initially identified through trio-WES, was confirmed using Sanger sequencing performed as part of the standard clinical validation procedure. Bioinformatic analysis involved the following filtering steps: (1) the sequenced reads were aligned to the reference genome (GRCh38/hg38); (2) variant calling and annotation were performed using the GATK best practices pipeline and the ANNOVAR software; (3) variants were prioritized based on population frequency (gnomAD allele frequency <0.1%), impact of mutations (nonsense, frameshift, and splice-site) on protein function, and inheritance models (X-linked); and (4) the identified FLNA variant was cross-referenced against ClinVar and analyzed using in silico prediction tools.

Variant interpretation was performed following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines (Richards et al., 2015). The FLNA c.5265C>G (p.Tyr1755*) variant was classified as “likely pathogenic” based on the application of evidence codes PVS1 (null variant in a gene where loss-of-function is a known mechanism of disease development), PM2 (absent in controls), and PP3 (deleterious based on in silico prediction). Segregation analysis confirmed maternal inheritance.

3.3 Literature review and statistical analysis

A systematic literature search was conducted on PubMed, including articles published until May 2025. The search terms included “FLNA mutations,” “periventricular nodular heterotopia,” “congenital short bowel syndrome,” “filamin A AND lung disease,” “FLNA AND male,” and “FLNA AND nonsense mutation.” Studies were included if they reported male patients with pathogenic FLNA variants and described associated phenotypes. Reviews and studies without clear genotype–phenotype correlations were excluded. A total of 62 cases from 30 publications were included in the qualitative synthesis, and associations between the various mutation types and clinical phenotypes were evaluated using Fisher’s exact test (applied to contingency tables), a suitable choice for the sample size. Statistical significance was defined as two-tailed P < 0.05.

4 Discussion

We report the case of a male infant with an FLNA nonsense mutation (c.5265C>G; p.Tyr1755*), whose phenotype was characterized by the canonical features of bilateral PNH, a perimembranous VSD, and congenital short bowel syndrome (CSBS). These findings, confirmed using genetic testing, are consistent with those of a loss-of-function variant. Beyond this established spectrum, the clinical course of the patient was complicated by nonspecific but life-threatening sequelae, such as recurrent infections with multidrug-resistant organisms and NEC, leading to fatal sepsis and multi-organ failure, likely driven by the underlying multisystem pathology and potential immune dysfunction.

The core phenotypic triad of PNH, CHD, and CSBS observed in our patient is highly suggestive of FLNA haploinsufficiency. The absence of FLNA has been reported to cause embryonic lethality and severe malformations in knockout mice (Feng et al., 2006; Stossel, 2010). FLNA alterations show diverse phenotypes depending on the molecular mechanism. Truncating mutations are predominantly observed in female patients because they are often lethal in male individuals. Male patients more commonly harbor mosaic, missense, splice-site, or distal truncating variants, aligning with our review of 62 cases of male individuals with FLNA mutation (Table 1 summarizes data from the Supplementary Material). Although no genotype–phenotype correlation was evident in the distribution of FLNA mutations (Fennell et al., 2015), our analysis of 62 cases yielded two key findings. First, despite a broad phenotypic spectrum, intestinal and skeletal manifestations are the most prevalent and most strongly associated with specific variant types (CNV/frameshift and in-frame deletion/missense, respectively). Second, protein-truncating variants (nonsense, frameshift, and splicing) are indicative of a more severe prognosis, including extensive multi-organ disease and high mortality. These insights are crucial for risk assessment and patient management. Nonsense mutations that introduce premature stop codons and trigger nonsense-mediated mRNA decay, similar to the mutation observed in our case, are often associated with severe cellular dysfunction and worse clinical outcomes compared to most other mutations (Lombardi et al., 2022; Patro et al., 2024). Our patient had a small intestine shorter than that of a full-term infant (190–280 cm) (Siebert, 1980) and had a loss-of-function mutation in FLNA (c.5265C>G) in exon 31, resulting in a stop codon at amino acid 1755 (p.Y1755*). Three-dimensional protein modeling demonstrated that the p.Tyr1755* mutation results in a “tailless” protein incapable of dimerization, thereby rendering it nonfunctional and providing a mechanistic basis for the severe clinical presentation (Figure 4). This profound protein dysfunction underlies structural anomalies and may have predisposed our patient to the severe complications observed during the clinical course. Without directly assessing FLNA protein levels in affected tissues, we cannot draw causal conclusions. Additionally, nonsense mutations often affect multiple systems, as observed in our patient, leading to complex clinical manifestations that are difficult to treat and result in a poor prognosis. These findings suggest a correlation between nonsense mutations and worse clinical outcomes. Although our analysis is descriptive and definitive conclusions are difficult to draw, the observed patterns may guide future studies with larger samples.

Table 1

Table 1. Genotype–phenotype correlations in FLNA-related disorders: organ-specific manifestations stratified by variant type among 62 male patients.

Figure 4

Figure 4. Structural localization of the FLNA variant p.Tyr1755*. The schematic illustrates the location of the premature termination codon (p.Tyr1755*) within the domain architecture of FLNA (transcript NM_001456.4). This static representation was generated using PyMOL (v3.1, Schrödinger) based on the wild-type FLNA structure (AF-P21333-F1, AlphaFold DB); it is intended to visually contextualize the variant. It is not a dynamic functional prediction but aids in hypothesizing potential effects on protein structure. Abbreviations: Tyr, tyrosine.

The contributions of FLNA to intestinal and pulmonary functions have been widely studied (Nhan et al., 2024; Sasaki et al., 2019). FLNA is present in cells of the small intestinal muscle layer from early fetal stages, specifically in the smooth muscle cells of the muscularis mucosa and propria. It plays a crucial role in signaling for smooth muscle contractility, essential for normal intestinal function, as demonstrated in animal models (Zada et al., 2023). Although FLNA is important for normal small intestinal development (Kapur et al., 2010; van der Werf et al., 2013), its precise role in intestinal development remains unclear (Feng et al., 2006; van der Werf et al., 2015). CSBS is a rare congenital gastrointestinal disease with a poor prognosis in infants, thought to result from interrupted fetal intestinal development owing to limited space in the umbilical cord, vascular issues, or volvulus (Hamilton et al., 1969; Kern et al., 1990). It is also associated with mutations in CXADR-like membrane protein (CLMP) and FLNA, both crucial for intestinal elongation (Chuang et al., 2020). Seventy cases have been documented to date, with FLNA mutations being less common than CLMP mutations in fully genotyped patients (Negri et al., 2020; van der Werf et al., 2012; 2013; 2015). The longer form of FLNA is essential for normal small intestinal development (Nhan et al., 2024). Some male survivors carrying FLNA loss-of-function mutations retain sufficient FLNA protein expression to avoid the lethal effects (Oda et al., 2016). CLMP mutations mainly affect the intestines, whereas FLNA mutations affect multiple systems and are associated with PNH (Robertson et al., 2003). Male patients with CSBS and FLNA mutations frequently exhibit multiple congenital anomalies (Van der Werf et al., 2013), as did our patient. Beyond these canonical features, our patient’s clinical trajectory was marked by complications that, while less specific, were critical. The development of refractory NEC and recurrent bloodstream infections likely stems from a confluence of factors. Small intestinal bacterial overgrowth and inflammation are well-established in patients with CSBS (Cole et al., 2010), possibly contributing to refractory NEC in our patient, whereas recurrent sepsis with multidrug-resistant organisms may indicate immune dysfunction. Neutrophils are vital in the early immune response by releasing reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) to combat pathogens. FLNA negatively regulates β2 integrin-dependent neutrophil adhesion and ROS production, and its depletion reduces NET release (Uotila et al., 2017). Reportedly, FLNA enhances β2 integrin-mediated immunosuppression, while lower FLNA levels might hinder transcription factor activation and interleukin-2 production by disrupting PKC translocation, potentially weakening the immune response (Hayashi and Altman, 2006; Uotila et al., 2017). Thus, the recurrent sepsis in our patient may indicate an underlying mutation-related immune deficit. However, the specific role of FLNA in immune defense remains unclear, and further assessment was not possible in this study. Further research is needed to elucidate the role of FLNA in immune dysregulation, which may facilitate the development of prospective therapeutic strategies.

Childhood interstitial lung disease, caused by genetic, immunological, and developmental lung issues, leads to interstitial lung abnormalities and impaired gas exchange, complicating diagnosis and classification (Kurland et al., 2013; O’Reilly et al., 2015). Most symptoms occur at infancy, in particular, unexplained respiratory distress in full-term neonates (O’Reilly et al., 2015), as observed in our patient. Male patients with respiratory phenotypes associated with rare FLNA loss-of-function mutations can survive into infancy owing to residual protein function but often experience a severe course (Desnous et al., 2024). De Wit et al. (2011b) first reported lung disease in patients with FLNA mutation. Patients with lung diseases related to FLNA mutations have a higher incidence of pneumonia, lung developmental defects, and respiratory failure, which can manifest at infancy (Sasaki et al., 2019). Abnormal FLNA interactions affect pulmonary viscoelastic properties and impair alveolar formation and growth (Meliota et al., 2022). Our patient had a slightly lower birth weight for gestational age and pulmonary hypoplasia requiring surfactant replacement therapy. Repeated imaging findings suggested emphysematous changes in the lungs. Additionally, the patient experienced recurrent respiratory failure at 2 months of age, with imaging findings suggestive of interstitial lung abnormalities. Similarly, Kinane et al. (2017) reported multiple unsuccessful extubation attempts. Cardiac color Doppler ultrasound of our patient revealed an increased pulmonary artery forward flow velocity, potentially indicating early pulmonary hypertension (PH), a rare manifestation in carriers of FLNA mutations (Hirashiki et al., 2017; Kinane et al., 2017). Pulmonary computed tomography and invasive hemodynamic assessment via catheterization were deferred owing to the high-risk condition of the patient and heightened radiosensitivity of infant tissues, and also based on the as-low-as-reasonably-achievable principle. Nevertheless, his persistent lung disease and hypoxemic respiratory failure, which are recognized in FLNA-related disorders, may have contributed to the development of PH and created a vicious cycle of clinical decline. Owing to the poor prognosis of PH, genetic testing is advised for pediatric cases. Moreover, pre-transplant evaluation may be considered, as CHD in FLNA-related disorders can complicate PH diagnosis (Demirel et al., 2018).

We discovered a novel loss-of-function mutation in FLNA associated with multi-organ involvement in a male patient, particularly atypical respiratory and gastrointestinal symptoms. This finding expands the phenotypic range of FLNA-related disorders, suggesting a role for FLNA in lung development, intestinal motility, and immune function. However, the lack of assessment of FLNA expression in intestinal tissues, quantitative assessment of immune cell functionality, and functional validation of FLNA—including measurement of residual protein expression—restricts causal conclusions. Furthermore, morphological features were not documented photographically owing to the patient’s demise, preventing visual validation. Future studies should delve deeper into the potential role of FLNA in the involved organ systems and determine whether earlier interventions could have changed the reported outcomes.

In conclusion, this case expands the phenotypic spectrum of a rare FLNA nonsense mutation by delineating between well-established, typical manifestations and severe, nonspecific complications that likely represent the downstream effects of multisystem failure and immune dysregulation. This distinction refines the phenotypic map of FLNA-related disorders and underscores the importance of vigilant multi-organ surveillance and early aggressive management in affected patients.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by the Ethics Review Committee of West China Second University Hospital, Sichuan University (Approval Code: KJ-2017-046-4). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants' legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

Author contributions

JL: Conceptualization, Writing – review and editing, Writing – original draft, Software, Investigation. XP: Writing – original draft, Writing – review and editing. LQ: Writing – review and editing, Investigation, Conceptualization. YL: Software, Writing – review and editing, Validation. ZL: Supervision, Validation, Writing – review and editing, Conceptualization, Visualization, Project administration, Formal Analysis, Writing – original draft.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Science and Technology Bureau of Sichuan province (No. 2019YFS0241).

Acknowledgements

We thank Professor Deyuan Li for his valuable suggestions and discussions. We are also grateful to our colleagues, Lu Li, Lijun Zhang, and Xiaoli He, from the Pediatric Intensive Care Unit of West China Second University Hospital, for their guidance and support in preparing this manuscript.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2025.1693117/full#supplementary-material

Footnotes

^{Abbreviations:}CHD, congenital heart disease; CSBS, congenital short bowel syndrome; CLMP, CXADR-like membrane protein; FLNA, filamin A; MRI, magnetic resonance imaging; MIC, minimum inhibitory concentration; NEC, necrotizing enterocolitis; NET, neutrophil extracellular trap; PICU, pediatric intensive care unit; PNH, periventricular nodular heterotopia; PH, pulmonary hypertension; ROS, reactive oxygen species; VSD, ventricular septal defect; WES, whole-exome sequencing.

References

Chuang, Y. H., Fan, W. L., Chu, Y. D., Liang, K. H., Yeh, Y. M., Chen, C. C., et al. (2020). Whole-exome sequencing identified novel CLMP mutations in a family with congenital short bowel syndrome presenting differently in two probands. Front. Genet. 11, 574943. doi:10.3389/fgene.2020.574943

PubMed Abstract | CrossRef Full Text | Google Scholar

Cole, C. R., Frem, J. C., Schmotzer, B., Gewirtz, A. T., Meddings, J. B., Gold, B. D., et al. (2010). The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J. Pediatr. 156, 941–947.e1. doi:10.1016/j.jpeds.2009.12.008

PubMed Abstract | CrossRef Full Text | Google Scholar

De Wit, M. C., de Coo, I. F., Lequin, M. H., Halley, D. J., Roos-Hesselink, J. W., and Mancini, G. M. (2011a). Combined cardiological and neurological abnormalities due to filamin A gene mutation. Clin. Res. Cardiol. 100, 45–50. doi:10.1007/s00392-010-0206-y

PubMed Abstract | CrossRef Full Text | Google Scholar

De Wit, M. C., Tiddens, H. A., de Coo, I. F., and Mancini, G. M. (2011b). Lung disease in FLNA mutation: confirmatory report. Eur. J. Med. Genet. 54, 299–300. doi:10.1016/j.ejmg.2010.12.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Demirel, N., Ochoa, R., Dishop, M. K., Holm, T., Gershan, W., and Brottman, G. (2018). Respiratory distress in a 2-month-old infant: is the primary cause cardiac, pulmonary or both? Respir. Med. Case Rep. 25, 61–65. doi:10.1016/j.rmcr.2018.06.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Desnous, B., Carles, G., Riccardi, F., Stremler, N., Baravalle, M., El-Louali, F., et al. (2024). Diffuse interstitial lung disease in a Male fetus with periventricular nodular heterotopia and filamin A mosaic variant. Prenat. Diag 44, 364–368. doi:10.1002/pd.6505

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, Y., Chen, M. H., Moskowitz, I. P., Mendonza, A. M., Vidali, L., Nakamura, F., et al. (2006). Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc. Natl. Acad. Sci. U.S.A. 103, 19836–19841. doi:10.1073/pnas.0609628104

PubMed Abstract | CrossRef Full Text | Google Scholar

Fennell, N., Foulds, N., Johnson, D. S., Wilson, L. C., Wyatt, M., Robertson, S. P., et al. (2015). Association of mutations in FLNA with craniosynostosis. Eur. J. Hum. Genet. 23, 1684–1688. doi:10.1038/ejhg.2015.31

PubMed Abstract | CrossRef Full Text | Google Scholar

Hamilton, J. R., Reilly, B. J., and Morecki, R. (1969). Short small intestine associated with malrotation: a newly described congenital cause of intestinal malabsorption. Gastroenterology 56, 124–136. doi:10.1016/s0016-5085(69)80074-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Hayashi, K., and Altman, A. (2006). Filamin A is required for T cell activation mediated by protein kinase C-theta. J. Immunol. 177, 1721–1728. doi:10.4049/jimmunol.177.3.1721

PubMed Abstract | CrossRef Full Text | Google Scholar

Hirashiki, A., Adachi, S., Nakano, Y., Kamimura, Y., Ogo, T., Nakanishi, N., et al. (2017). Left main coronary artery compression by a dilated main pulmonary artery and left coronary sinus of valsalva aneurysm in a patient with heritable pulmonary arterial hypertension and FLNA mutation. Pulm. Circ. 7, 734–740. doi:10.1177/2045893217716107

PubMed Abstract | CrossRef Full Text | Google Scholar

Kapur, R. P., Robertson, S. P., Hannibal, M. C., Finn, L. S., Morgan, T., van Kogelenberg, M., et al. (2010). Diffuse abnormal layering of small intestinal smooth muscle is present in patients with FLNA mutations and x-linked intestinal pseudo-obstruction. Am. J. Surg. Pathol. 34, 1528–1543. doi:10.1097/PAS.0b013e3181f0ae47

PubMed Abstract | CrossRef Full Text | Google Scholar

Kern, I. B., Leece, A., and Bohane, T. (1990). Congenital short gut, malrotation, and dysmotility of the small bowel. J. Pediatr. Gastr. Nutr. 11, 411–415. doi:10.1097/00005176-199010000-00023

PubMed Abstract | CrossRef Full Text | Google Scholar

Kinane, T. B., Lin, A. E., Lahoud-Rahme, M., Westra, S. J., and Mark, E. J. (2017). Case 4-2017. A 2-month-old girl with growth retardation and respiratory failure. New Engl. J. Med. 376, 562–574. doi:10.1056/NEJMcpc1613465

PubMed Abstract | CrossRef Full Text | Google Scholar

Kurland, G., Deterding, R. R., Hagood, J. S., Young, L. R., Brody, A. S., Castile, R. G., et al. (2013). An official American thoracic society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am. J. Resp. Crit. Care 188, 376–394. doi:10.1164/rccm.201305-0923ST

PubMed Abstract | CrossRef Full Text | Google Scholar

Lombardi, S., Testa, M. F., Pinotti, M., and Branchini, A. (2022). Translation termination codons in protein synthesis and disease. Adv. Protein Chem. Str. 132, 1–48. doi:10.1016/bs.apcsb.2022.06.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Meliota, G., Vairo, U., Ficarella, R., Milella, L., Faienza, M. F., and D'Amato, G. (2022). Cardiovascular, brain, and lung involvement in a newborn with a novel FLNA mutation: a case report and literature review. Adv. Neonat. Care. 22, 125–131. doi:10.1097/ANC.0000000000000878

PubMed Abstract | CrossRef Full Text | Google Scholar

Negri, E., Coletta, R., and Morabito, A. (2020). Congenital short bowel syndrome: systematic review of a rare condition. J. Pediatr. Surg. 55, 1809–1814. doi:10.1016/j.jpedsurg.2020.03.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Nhan, V. T., Hoang, T. V., Nhan, P. N. H., Huynh, Q. T. V., and Ban, H. T. (2024). Congenital short bowel syndrome: cases series in the same family and review of literature. Int. J. Surg. Case Rep. 123, 110135. doi:10.1016/j.ijscr.2024.110135

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Reilly, R., Kilner, D., Ashworth, M., and Aurora, P. (2015). Diffuse lung disease in infants less than 1 year of age: histopathological diagnoses and clinical outcome. Pediatr. Pulm. 50, 1000–1008. doi:10.1002/ppul.23124

CrossRef Full Text | Google Scholar

Oda, H., Sato, T., Kunishima, S., Nakagawa, K., Izawa, K., Hiejima, E., et al. (2016). Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function. Eur. J. Hum. Genet. 24, 408–414. doi:10.1038/ejhg.2015.119

PubMed Abstract | CrossRef Full Text | Google Scholar

Patro, I., Sahoo, A., Nayak, B. R., Das, R., Majumder, S., and Panigrahi, G. K. (2024). Nonsense-mediated mRNA decay: mechanistic insights and physiological significance. Mol. Biotechnol. 66, 3077–3091. doi:10.1007/s12033-023-00927-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Reinstein, E., Frentz, S., Morgan, T., García-Miñaúr, S., Leventer, R. J., McGillivray, G., et al. (2013). Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in filamin A. Eur. J. Hum. Genet. 21, 494–502. doi:10.1038/ejhg.2012.209

PubMed Abstract | CrossRef Full Text | Google Scholar

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical Genetics and genomics and the association for molecular pathology. Genet. Med 17 (5), 405–424. doi:10.1038/gim.2015.30

PubMed Abstract | CrossRef Full Text | Google Scholar

Robertson, S. P., Twigg, S. R., Sutherland-Smith, A. J., Biancalana, V., Gorlin, R. J., Horn, D., et al. (2003). Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat. Genet. 33, 487–491. doi:10.1038/ng1119

PubMed Abstract | CrossRef Full Text | Google Scholar

Sasaki, E., Byrne, A. T., Phelan, E., Cox, D. W., and Reardon, W. (2019). A review of filamin A mutations and associated interstitial lung disease. Eur. J. Pediatr. 178, 121–129. doi:10.1007/s00431-018-3301-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Sheen, V. L., Jansen, A., Chen, M. H., Parrini, E., Morgan, T., Ravenscroft, R., et al. (2005). Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 64, 254–262. doi:10.1212/01.WNL.0000149512.79621.DF

PubMed Abstract | CrossRef Full Text | Google Scholar

Siebert, J. R. (1980). Small-intestine length in infants and children. Am. J. Dis. Child. 134, 593–595. doi:10.1001/archpedi.1980.02130180051015

PubMed Abstract | CrossRef Full Text | Google Scholar

Stossel, T. P. (2010). Filamins and the potential of complexity. Cell Cycle 9, 1463–1465. doi:10.4161/cc.9.8.11462

PubMed Abstract | CrossRef Full Text | Google Scholar

Uotila, L. M., Guenther, C., Savinko, T., Lehti, T. A., and Fagerholm, S. C. (2017). Filamin A regulates neutrophil adhesion, production of reactive oxygen species, and neutrophil extracellular trap release. J. Immunol. 199, 3644–3653. doi:10.4049/jimmunol.1700087

PubMed Abstract | CrossRef Full Text | Google Scholar

Van Der Werf, C. S., Wabbersen, T. D., Hsiao, N. H., Paredes, J., Etchevers, H. C., Kroisel, P. M., et al. (2012). CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome. Gastroenterology 142, 453–462.e453. doi:10.1053/j.gastro.2011.11.038

PubMed Abstract | CrossRef Full Text | Google Scholar

Van der Werf, C. S., Sribudiani, Y., Verheij, J. B., Carroll, M., O'Loughlin, E., Chen, C. H., et al. (2013). Congenital short bowel syndrome as the presenting symptom in Male patients with FLNA mutations. Genet. Med. 15, 310–313. doi:10.1038/gim.2012.123

PubMed Abstract | CrossRef Full Text | Google Scholar

Van der Werf, C. S., Halim, D., Verheij, J. B., Alves, M. M., and Hofstra, R. M. (2015). Congenital short bowel syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation. Biochim. Biophys. Acta 1852, 2352–2361. doi:10.1016/j.bbadis.2015.08.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Zada, A., Zhao, Y., Halim, D., Windster, J., van der Linde, H. C., Glodener, J., et al. (2023). The long Filamin-A isoform is required for intestinal development and motility: implications for chronic intestinal pseudo-obstruction. Hum. Mol. Genet. 32, 151–160. doi:10.1093/hmg/ddac199

PubMed Abstract | CrossRef Full Text | Google Scholar