Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.

doi:10.21203/rs.3.rs-4546691/v1

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Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.

https://doi.org/10.21203/rs.3.rs-4546691/v1

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BACKGROUND

Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. Gain-of-function (GOF) variants in FLNA are associated with oto-palato-digital spectrum disorders (OPDSD). Loss-of-function (LOF) variants give rise to a wide variety of symptoms with periventricular nodular heterotopia (PVNH) and epilepsy as the most common features. FLNA deficiency manifests as a multisystemic disorder with abnormalities of connective tissue and involvement of the cardiovascular, pulmonary, gastrointestinal and hematological system. Affected individuals need a multidisciplinary follow-up, but guidelines are lacking. Here, we present findings from a monocentric cross-sectional cohort study as a basis for improving clinical practices and surveillance for individuals with pathogenic FLNA variants.

RESULTS

The FLNA-cohort consisted of 24 index patients with a pathogenic (class 5) LOF variant in FLNA. In the cohort, 23 patients exhibited clinical features of PVNH, while one individual manifested congenital pulmonary airway malformation (CPAM). The incidence of clinical features such as epilepsy (84%) and cardiovascular involvement (56%) are consistent with previously published cohorts. Systematic multidisciplinary follow-up, particularly regular cardiological screening, was lacking in a significant number of individuals. Additionally, lesser-known symptoms such as constipation and thrombocytopenia were underreported, highlighting the need for comprehensive phenotypic assessment in FLNA deficiency.

CONCLUSION

The incidence of clinical features in this tertiary cohort aligns with existing literature. The absence of uniform and multidisciplinary guidelines hampers effective surveillance and management. Implementation of regular cardiological screening and increased awareness of less overt symptoms could enhance medical outcomes for individuals with pathogenic FLNA variants.

Filamin A (FLNA)

Periventricular nodular heterotopia

Neuronal migration disorder

Malformation of Cortical Development

Genetic counseling

Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration. FLNA is a key player during neuronal migration and a wide variety of other biological processes such as skeletal development and organization of the extracellular matrix. The FLNA gene is located on the X chromosome, comprising 48 exons. Pathogenic variants in FLNA follow an X-linked dominant inheritance pattern.(1) Both gain-of-function (GOF) variants and loss-of-function (LOF) variants are described in the FLNA gene, each associated with a distinct phenotype. GOF variants result in oto-palato-digital spectrum disorders (OPDSD) and are mainly located in the OPD-cluster of exons 3–5. Characteristic features for OPDSD include facial dysmorphisms, limb anomalies, hearing loss (due to bone defects), cleft palate and skeletal dysplasia.(2) LOF variants can be found over almost the entire gene and are predominantly associated with periventricular nodular heterotopia (PVNH) but can affect multiple organ systems.(3, 4) This cohort study focuses on FLNA deficiency resulting from LOF variants and its multisystemic involvement.

Most LOF variants in FLNA result in PVNH. FLNA is a key player of the neuronal migration process during embryogenesis. The link between FLNA, formerly known as FLN1, and PVNH was first described by Fox et al. (1998).(5) In FLNA deficiency, cortical neurons expressing the pathogenic variant fail to migrate into the developing cortex and remain as nodules at the ventricular surface. In females, approximately fifty percent of neurons fail to migrate correctly because of random X-chromosome inactivation, described on MRI as PVNH.(6, 7) In addition to the previously mentioned PVNH, other common anomalies on MRI are fossa posterior anomalies including mega cisterna magna (observed in 33–93% of cases), and abnormalities affecting the corpus callosum (seen in 33–40% of cases).(3, 8) Furthermore, individuals with FLNA deficiency frequently exhibit neurological manifestations such as autism spectrum disorder and dyslexia.(9)

Besides PVNH and neurologic symptoms, FLNA deficiency also affects the cardiovascular system. Aortic root dilation and dissection, along with valvular dysfunction and additional anomalies, commonly co-occur, originating from underlying structural and connective tissue involvement.(10–14) Lastly, the gastrointestinal, as well as the pulmonary and hematological systems can also be affected in FLNA deficiency.(3, 15–20) Table 1 provides an overview of the FLNA-deficient phenotype per organ system.

Table 1

Phenotypical findings in FLNA deficiency.
ORGAN SYSTEM	ASSOCIATED PHENOTYPE
Neurologic	- Periventricular nodular heterotopia (PVNH) with high risk for epilepsy - Autism spectrum disorder - Dyslexia - (Mild) Intellectual disability - Migraine
Cardiovascular	- Arterial dilation and aneurysm including aortic dilation and aneurysm and sinus of Valsalva aneurysm, pulmonary artery dilation, arterial tortuosity - Valves: bicuspid aortic valve, aortic-, mitral-, pulmonal- and tricuspid valve dysfunction - Patent ductus arteriosus (PDA) - Ventricular and atrial sepal defects (VSD, ASD) - Early onset of varicose veins
Pulmonary	- Emphysema, including congenital pulmonary airway malformation (CPAM) - Bronchopulmonary dysplasia - Interstitial lung disease
Gastrointestinal	- Congenital short bowel - Chronic intestinal pseudo-obstruction (CIPO) - Constipation
Connective tissue (except cardiovascular anomalies) Ehler -Danlos-like phenotype	- Joint hyperlaxity - Skin hyper elasticity - Cutaneous fragility (scarring) - Spontaneous or easy bruising - Abdominal wall hernia (e.g. umbilical hernia)
Other	- Macrothrombocytopenia - Single umbilical artery

FLNA deficiency is a rare disorder. The true incidence remains unknown since a substantial part of individuals with a pathogenic variant are ‘asymptomatic’, without clinically overt symptoms. These ‘asymptomatic’ individuals may never seek medical attention, yet they remain prone to silent symptoms of FLNA deficiency such as aortic root dilation and dissection. Substantial morbidity and mortality have been associated with FLNA deficiency.(14) Patients require a multidisciplinary follow-up, but consensus recommendations or guidelines are lacking.

The aim of this retrospective study is to delineate the clinical phenotype, genotype and medical follow-up of the FLNA deficiency cohort at UZ Brussel hospital as a basis for improving clinical practice. The cohort consists of individuals with follow-up at UZ Brussel and external patients referred for genetic testing. In all individuals the molecular diagnosis was established by using different techniques including Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and Next Generation Sequencing (NGS) based panels for malformations of cortical development (MCD).

Clinical data regarding genotype, phenotype and follow-up were collected from referring physicians and patient records. Comparative analysis of clinical findings was performed against existing literature using descriptive statistical methods.

We identified 26 index patients with a pathogenic (class 5) LOF variant in FLNA. Two patients were excluded due to insufficient clinical data, resulting in 24 individuals eligible for inclusion. All 24 variants are listed in Table 2. LOF variants are distributed throughout the protein with no predictive correlation between variant location and phenotype severity. The variants of patients 9, 14 and 23 have been previously published (respectively González-Morón et al., Hu et al. and Gérard-Blanluet et al.).(21–23) Extended clinical information was available for sixteen individuals, three patients were fetuses and for five individuals clinical information was incomplete. Table 3 provides a summary of the clinical features observed in the included individuals.

Table 2

Summary of genetic information of 27 index patients, ordered by genetic position. Patients 11, 14 and 19 are male patients.
INDIVIDUAL	GENOTYPE – VARIANT DISTRIBUTION	VARIANT TYPE	PHENOTYPE
1	Gene deletion (MLPA)	/	PVNH
2	c.296T > C, p.(Phe99Ser)	Missense	PVNH
3	c.1196_1199dup, p.(Thr401Glnfs*6)	Frameshift	PVNH
4	c.1489 del, p.(Val 497*)	Frameshift	PVNH
5	c.1737dupA, p.(Arg580 Thrfs*41)	Frameshift	PVNH
6	c.1923 C > T	Splice site variant	PVNH
7	c.1972_1990del, p.(Pro658Valfs*12)	Frameshift	CPAM
8	c.1990delC, p.(Arg664Valfs*12)	Frameshift	PVNH
9	c.2193C > G, p.(Tyr731*)	Nonsense	PVNH
10	c.2247G > A, p.(Trp749*)	Nonsense	PVNH
11	c.2449C > T, p.(Pro817Ser)	Missense	PVNH (Male)
12	c.3678dup, p.(Gly1227Argfs*40)	Frameshift	PVNH
13	c.4142 + 1dlG	Splice site variant	PVNH
14	c.4451A > G, p.(Gln1484Arg)	Missense	PVNH (Male)
15	c.4993C > T, p.(Gln1665*)	Nonsense	PVNH
16	c.5209C > T, p.(Gln1737*)	Nonsense	PVNH
17	c.5766_5767dup, p.(Ser1923Cysfs*14)	Frameshift	PVNH
18	c.5800del, p.(Ile1934Phefs*2)	Frameshift	PVNH
19	c.5991T > A, p.(Cys1997*)	Nonsense	PVNH (Male fetus)
20	c.6150dup, p.(Arg2051Serfs14) MOSAIC (16% of reads)*	Frameshift	PVNH
21	c.6915C > A, p.(Tyr2305*)	Nonsense	PVNH
22	c.6930delG, p.(Lys2310Asnfs*36)	Frameshift	PVNH
23	c.7922C > T, p.(Pro2641Leu)	Missense	PVNH
24	Del exon 38–46 (MLPA)	Multiple exon deletion	PVNH

Table 3

Age, gender (F = Female, M = Male) and phenotype of index patients with LOF variants (FLNA deficiency).
	ID	Age, Gender	PVNH	Other brain malformations	Epilepsy	Other neurologic features	Cardiovascular manifestations	Gastro-intestinal manifestations	Pulmonary manifestations	Connective tissue	Other
1	D12.0851	13y, F	YES	Mega cisterna magna	YES
2	D15.1710	Fetus, F	YES	Ventriculomegaly	NA	NA	NA	NA	NA	NA	NA
3	D13.0703	17y, F	YES	Mega cisterna magna	YES	Mild developmental delay, autism, Developmental Coordination Disorder	Aortic valve insufficiency, dilatation of the aortic root			Umbilical hernia	Single umbilical artery
4	D13.0731	46y, F	YES		YES		Aortic valve insufficiency	Gallbladder cyst
5	D13.2395	15y, F	YES		YES	Mild developmental delay, autism		Constipation	Asthma
6	D15.2941	68y, F	YES		YES		Discrete Tricuspid valve insufficiency
7	D18.4253	5y, F	NO		NO		PDA		CPAM, asthma
8	D14.1624	38y, F	YES	Mega cisterna magna	YES	ADHD, migraine
9	D16.5703	50y, F	YES	Mega cisterna magna, cerebellar arachnoid cyst	YES		Fallot tetralogy, aorta aneurysm and dissection
10	D23.2979	25y, F	YES		NO	migraine					Thrombocytopenia
11	D12.3716	12y, M	YES	Thin corpus callosum, thin n. optici	YES, encephalopathy	Developmental delay, autism	UNKNOWN	Constipation	Asthma	Soft skin, achromatic patches	Easy bruising
12	D15.5773	9y, F	YES		NO	Mild developmental delay	UNKNOWN			Umbilical hernia
13	D16.3101	62y, F	YES	Hypoplastic corpus callosum, arachnoid cyst posterior fossa	YES	ADD	Aortic and mitral valve insufficiency	Constipation		Ehlers-Danlos-like phenotype (vascular type)	Thrombocytopenia, easy bruising
14	D16.4374	30y, M	YES	Left parietal closed lip Schizencephaly	YES
15	D19.7614	49y, F	YES		YES	Migraine					Meningioma at age 47
16	D14.3657	23y, F	YES	UNKNOWN	YES	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN
17	D20.1214	52y, F	YES		YES		VSD (corrected), mild aortic and mitral valve insufficiency
18	D17.6528	6y, F	YES	Agenesis corpus callosum	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN
19	D14.1760	Fetus, M	YES	Mega cisterna magna	NA	NA	NA	NA	NA	NA	NA
20	D20.3522	33y, F	YES		YES	Migraine	Aortic valve insufficiency
21	D22.6744	16y, F	YES	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN	UNKNOWN
22	D14.1175	12y, F	YES	Insular polymicrogyria, thin corpus callosum, cerebellar arachnoid cyst	YES	Dyslexia
23	D14.5002	33y, F	YES		YES		sinus of Valsalva aneurysm	CIPO			Hypothyroidism
24	D18.00234	Fetus, F	YES	Mega cisterna magna	NA	NA	NA	NA	NA	NA	NA
	TOTAL		23/24 (= 95%)		16/19 (= 84%) 3 NA 2 UNKNOWN		9/16 (= 56%) 3 NA 5 UNKNOWN	3 patients with constipation, 1 with CIPO (4/16, 25%)	1 patient with CPAM and asthma, 2 patients with asthma (3/16, 19%)	4 patients with connective tissue involvement	2 patients with thrombocytopenia, 2 patients with easy bruising
	GENEREVIEWS				75–90%		65%	6%	25%	Prevalence not listed	Prevalence not listed

In our cohort, PVNH predominated, affecting 23 out of 24 patients. Commonly associated MRI findings, such as fossa posterior abnormalities, including mega cisterna magna, and an abnormal corpus callosum were identified in 33% and 18% of cases, respectively. Additionally, other observations included ventriculomegaly, closed lip schizencephaly, and insular polymicrogyria. Among nineteen patients with available data, epilepsy was prevalent in sixteen individuals (84%) with a median age of onset at 17 years and drug-resistance in 42%. Notably, patients 11 and 14, both male survivors with a PVNH phenotype, harbored missense variants. Cardiovascular involvement was noted in 56% (nine out of sixteen) of individuals with comprehensive cardiovascular evaluation. Valve insufficiency had the highest frequency and was observed in six patients, followed by aortic root involvement, noted in two patients. Other cardiological findings included Fallot tetralogy, patent ductus arteriosus (PDA), ventricular septal defect (VSD).

Three patients reported severe constipation, with one individual diagnosed with chronic intestinal pseudo-obstruction (CIPO) with total colectomy due to recurrent pseudo-obstructions. Patient 7 presented with congenital pulmonary airway malformation (CPAM) and underwent a pulmonary lobectomy at six months old; she concurrently experiences severe asthma. Additionally, two patients reported asthma, while thrombocytopenia was noted in two patients.

We report a monocentric study describing the clinical and molecular findings of 24 individuals. In the following sections, we first compare our finding to reported cases in literature and highlight some particular findings in our cohort. Furthermore, we will conclude with conclusions and recommendations regarding multidisciplinary follow-up in FLNA-deficient patients.

Neurological system

In this cohort, 23 out of 24 individuals have PVNH. PVNH in FLNA deficiency is typically bilateral and anteriorly predominant, as depicted in Fig. 1. Additional FLNA-related MRI findings are mega cisterna magna, abnormalities of the corpus callosum, subarachnoid cysts and deformed anterior horns of the lateral ventricles.(4, 8) A potential source of bias in this cohort is the proportion of individuals who are PNVH positive. The majority of these individuals were referred to our facility specifically for genetic testing (MCD panel) because of PNVH. This referral method may have influenced the composition of the cohort.

PVNH significantly predisposes individuals to epilepsy, with up to a 90% risk of developing seizures, particularly during early adolescence. In our cohort, epilepsy is prevalent in 84% of individuals (sixteen out of nineteen with available data), consistent with previous reports.(3, 24) There was insufficient information within this cohort for assessment of presenting features. However, existing literature indicates that in the majority of individuals with FLNA deficiency, epilepsy is the presenting symptom in 63–88% of cases.(3, 24)

In our cohort, mild developmental delays were noted in three female patients (patients 3, 5, and 12) and in one male patient (patient 11). Generally, individuals with FLNA deficiency exhibit normal intellectual capacities, although developmental delays have been documented. Lange et al. observed a higher occurrence of mild developmental delays in patients who experienced seizure onset during childhood, before the age of eleven. In our cohort, patients 3 and 5 experienced seizure onset at four and five years of age, respectively.(3) Patient 12, currently nine years old, does not have epilepsy at this moment. Patient 11 (male patient) exhibits severe developmental delays and early-onset encephalopathy. Additionally, Chang et al. reported that, despite having normal intellect, individuals with PVNH may experience deficits in reading skills in up to 80% of cases.(9) In our cohort, only one patient was diagnosed with dyslexia, suggesting that reading difficulties may be underrecognized.

Cardiovascular system

In our cohort, cardiovascular involvement was observed in 56% (nine out of sixteen) of individuals. Importantly, it's noted that many individuals underwent only a one-time cardiovascular screening post-genetic diagnosis, particularly "cardio-negative" patients without cardiovascular abnormalities. The study by De Wit et al. highlights the association between FLNA deficiency and cardiovascular involvement. Among 24 patients with bilateral PVNH, six had a LOF variant in FLNA. Strikingly, five of these FLNA-deficient patients exhibited notable cardiological manifestations, such as aortic dilation and mitral valve regurgitation. In contrast, none of the individuals in the group with bilateral PVNH lacking a pathogenic variant in FLNA demonstrated cardiovascular malformations or dysfunction. Literature reports cardiovascular features in up to 65% of FLNA-deficient individuals, which are often a combination of structural and connective tissue anomalies.(10–12) Chen et al. describe structural cardiac malformation, present in 57,1% of patients, most commonly patent ductus arteriosus and valvular abnormalities. Progressive dilation, particularly of the aortic root and ascending aorta, was present (18.4%) in both pediatric and adult individuals. Additionally, they describe two adult patients (1F, 1M, median 38.5y), died of spontaneous aortic rupture at aortic dimensions smaller than current recommendations for surgery for other aortopathies.(14) The progressive nature of aortic dilatation underscores the importance of periodic cardiological follow-up over time.

Other organ system involvement

Aside from neurological and cardiovascular involvement, other organ systems can also exhibit manifestations of FLNA deficiency as the presenting feature including pulmonary (CPAM) and gastrointestinal features (CIPO, congenital short bowel). While they are rare, the potential impact on health and outcomes can be significant.

Connective tissue

In our cohort four patients had connective tissue involvement of which two patients had an umbilical hernia and two patients had an Ehlers-Danlos-like phenotype with easy bruising. Historically, individuals presenting with PVNH, joint hyperlaxity, increased skin elasticity and aortic dilation were classified within the Ehlers-Danlos spectrum as a distinct entity known as Ehlers-Danlos with PVNH.(25) In 2017, Ehlers-Danlos with PVNH was excluded from the Ehlers-Danlos spectrum because of the predominant neurological symptoms.(13, 26) Prevalence data for connective tissue involvement in FLNA deficiency is not readily available in the literature; however, joint hyperlaxity is reported in less than 15% of cases.(3)

Pulmonary system

Progressive respiratory distress caused by CPAM was the presenting feature in patient 7 of our cohort. On MRI she had no PVNH and is therefore at lower risk for developing epilepsy. Asthma was reported in three patients, including patient 7, which aligns with the reported 25% pulmonary involvement documented in the review of Sasaki et al.(18) FLNA deficiency can cause respiratory symptoms such as interstitial lung disease, pulmonary dysplasia and emphysema by different mechanisms. They typically manifest with increasing respiratory distress during infancy, resulting in high morbidity and mortality rates due to respiratory failure and secondary heart failure.(18) The precise underlying mechanism remains unclear, but it is hypothesized that FLNA plays an important role in alveolar maturation and lung development.(19) Our findings align with the reported 25% pulmonary involvement documented in the review of Sasaki et al.(18)

Gastrointestinal system

We found in our cohort that 25% of the patients experience constipation with or without associated CIPO. At the gastroenterological level, FLNA is an important player in the function of the intestinal muscle layer. FLNA deficiency impairs the contractility of the smooth intestinal muscles, affecting the peristalsis.(20) Constipation is a common feature in FLNA-deficient individuals, reflecting impaired peristalsis. Additionally, more severe gastrointestinal complications such as CIPO and congenital short bowel syndrome have been associated with FLNA deficiency.(20) According to Langhe et al. only 6% of individuals suffer from gastrointestinal involvement.(3) Our findings might implicate that the association between constipation and FLNA deficiency is not well-known by physicians and that constipation is an underreported symptom in the FLNA-deficient population.

Hematological system

In our cohort, two individuals were reported to have thrombocytopenia. Platelet production is altered with enlarged alpha-granules and the platelet-vessel interaction is abnormal resulting in coagulopathy and thrombocytopenia. Patients are more susceptible to stroke because of vasculopathy and coagulopathy.(17) Prevalence data for macrothrombocytopenia in FLNA deficiency are currently unavailable in the literature.

Specific findings in the cohort

Surviving males

The X-linked dominant inheritance pattern of FLNA deficiency typically results in male fetuses being more severely affected, resulting in mors in utero and recurrent miscarriages in affected women. However, our cohort includes two male individuals with FLNA deficiency. Male individuals have been described in literature and can only survive when some residual FLNA function is present. This can be the result of a ‘milder’, hypomorphic variant such as missense variants or variants closer to the C-terminus of the protein, or the presence of a mosaic variant.(1, 15, 27–29) Both surviving male patients in our cohort with PVNH (patients 11 and 14) have germline missense variants and have more severe phenotypes compared to the female individuals. They both have developmental delay and patient 11 had early-onset encephalopathy with connective tissue and hematological involvement. Interestingly, the mother of patient 11 is heterozygous for the same variant as her son, yet her brain MRI was completely normal and she had no associated symptoms. This observation supports the presence of a hypomorphic variant, which is not pathogenic enough to affect females but mild enough to permit survival in males.

Mosaicism

Patient 20 had a pathogenic variant in 16% of the NGS reads (blood sample), confirming a mosaic state for FLNA. This female patient presented PVNH, epilepsy and aortic valve insufficiency, which is a comparable phenotype to patients with non-mosaic variants.(1, 28) A possible explanation for the complete phenotype despite the relatively low percentage of mosaicism in blood is the possibility of tissue-specific variations in the percentage of mosaicism. Higher levels of mosaicism may be present in brain and cardiac tissues compared to blood, potentially explaining the observed clinical findings.

MULTIDISCIPLINARY FOLLOW-UP

Ensuring appropriate medical follow-up is crucial for individuals with FLNA deficiency to optimize outcomes and address potential complications effectively. While yearly check-ups with a neurologist are recommended, cardiological follow-up is equally important, even in individuals with normal-sized aortas at initial evaluation. In those without evident cardiovascular issues ("cardio-negative" individuals), regular echocardiography every 1–2 years should be a standard point-of-care, complemented with cardiac CT or MRI as needed. Closer monitoring is warranted during childhood, periods of rapid growth, and pregnancy.(14)

Lesser-known associated symptoms, such as constipation, reading difficulties and thrombocytopenia are in general underrecognized as part of the FLNA-deficient phenotype and are therefore not frequently questioned at consultation. Improved awareness of the FLNA-deficient phenotype and standardized follow-up with focus on regular cardiological screening and yearly questioning of more subtle symptoms could improve medical outcome. A proposed multidisciplinary follow-up plan, outlined in Table 4 based on literature and expert opinion, can guide healthcare providers in coordinating multidisciplinary care for FLNA-deficient individuals. For those with primary pulmonary or gastrointestinal features, such as CPAM, CIPO, or congenital short bowel syndrome, specialized individualized care is essential.

Table 4

Screening tool for patients with FLNA deficiency and PVNH per organ system
FLNA Deficiency	Organ system	Problems to screen for	Intervention
	Neurological	Epilepsy Learning difficulties, concentration problems, behavioral problems	(nocturnal) EEG, epilepsy treatment if necessary Question on a yearly basis at consultation
	Cardiovascular	Valve insufficiency, aortic dilation, aneurysms	Cardiac echography	Previous echography was normal	Repeat echography every 1–2 years
				Previous echography was abnormal	Minimally once a year or more frequently on specialist advice
	Pulmonary	Asthma	Question on yearly basis at consultation
	Gastro-intestinal	Constipation	Question on yearly basis at consultation
	Connective tissue	Abdominal wall hernias, skin problems	Question on yearly basis at consultation
	Hematological	Prolonged bleeding (e.g. gum bleeding), excessive bruising, slow wound healing	Check thrombocytes every 3–5 years (combined with routine check-up) or sooner on indication

Centralized coordination of multidisciplinary follow-up, preferably through a center for rare diseases or a Center for Medical Genetics, can facilitate multidisciplinary care. However, in the absence of centralized consultation options, the (pediatric) neurologist can coordinate multidisciplinary follow-up to ensure optimal care. Non-profit organizations such as national rare disease organizations can play a crucial role in assisting individuals in finding appropriate care and providing support throughout and after the diagnostic process. Additionally, patient advocacy groups such as "PVNH Support & Awareness" (www.pvnhsupport.com) serve to foster connections within families, offer education, and advocate for patients, families, and healthcare practitioners. These organizations serve as pivotal interfaces between healthcare providers, patients, and their families.

The incidence of clinical features observed in this tertiary cohort aligns with incidences reported in previously published cohorts. However, to ensure comprehensive and effective multidisciplinary follow-up for every individual with a pathogenic FLNA variant, uniform guidelines are necessary. Neurological follow-up and epilepsy care should be complemented by regular cardiological screening, as well as proactive questioning of rare and subtle symptoms to optimize medical outcomes. We therefore advocate for a more systematic follow-up with attention for neurological, cardiovascular, pulmonary, hematological, gastrointestinal and hematologic aspects of the disease. A systematic approach to follow-up is warranted to provide holistic care.

ABBREVIATION	EXPLANATION
ADHD	Attention Deficit Hyperactivity Disorder
ASD	Atrial Septal Defect
CIPO	Chronic Intestinal Pseudo Obstruction
CPAM	Congenital Pulmonary Airway Malformation
FLNA	Filamin A
GOF	Gain-of-function
LOF	Loss-of-function
MCD	Malformation of Cortical Development
MLPA	Multiplex Ligation-dependent Probe Amplification
NGS	Next Generation Sequencing
OPDSD	Oto-Palato-Digital Spectrum Disorder
PDA	Patent Ductus Arteriosus
PVNH	Periventricular Nodular Heterotopia
VSD	Ventricular Septal Defect

Ethics approval: This retrospective study is approved by the Ethics Committee of the UZ Brussel BUN 1432023000206.

Data availability: All data generated or analyzed during this study are included in this published article.

Competing interests: The authors declare that they have no competing interests.

Funding: Ellen Rijckmans is funded by a research fellowship from the Marguerite-Marie Delacroix Foundation. Jessica Rosenblum is funded by the University of Antwerp, University Research Fund (BOF – 47075-DOCPRO_2022). Anna Jansen is supported by a Senior Clinical Investigator fellowship of the Research Foundation Flanders (FWO 1805321N).

Authors’ contributions: Data collection was performed by Ellen Rijckmans and Lars De Strooper. Ellen Rijckmans wrote the manuscript. Kathelijn Keymolen, Jessica Rosenblum, Bart Loeys, Marije Meuwissen, Anna Jansen, and Katrien Stouffs did proofreading of the manuscript.

Acknowledgements: We thank the contributing patients and physicians, the Marguerite-Marie Delacroix Foundation for supporting Ellen Rijckmans with a research grant. Finally, we thank Marije Meuwissen, who participates as the coordinator of HCP Antwerp in the European Reference Network ITHACA.

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Reviewers agreed at journal
23 Oct, 2024
Reviewers invited by journal
23 Oct, 2024
Editor assigned by journal
10 Jun, 2024
First submitted to journal
07 Jun, 2024

You are reading this latest preprint version

Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.

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Abstract

Figures

BACKGROUND

MATERIALS AND METHODS

RESULTS

DISCUSSION

Neurological system

Cardiovascular system

Other organ system involvement

Connective tissue

Pulmonary system

Gastrointestinal system

Hematological system

Specific findings in the cohort

Surviving males

Mosaicism

MULTIDISCIPLINARY FOLLOW-UP

CONCLUSIONS

Abbreviations

Declarations

References

Status:

Version 1