Fetal phenotypes in otopalatodigital spectrum disorders

Naudion, Sophie; Moutton, Sébastien; Coupry, Isabelle; Solé, Guilhem; Deforges, Julie; Guerineau, Elodie; Hubert, Cédric; Deves, S.; Pilliod, Julie; Rooryck, Caroline; Abel, C.; Breton, F. Le; Collardeau‐Frachon, Sophie; Cordier, Marie‐Pierre; Delezoide, Anne‐Lise; Goldenberg, Anna; Loget, Philippe; Melki, Judith; Odent, S.; Patrier, Sophie; Verloès, Alain; Viot, Géraldine; Blesson, Sophie; Bessières, Bettina; Lacombe, Didier; Arveiler, Benoı̂t; Goizet, Cyril; Fergelot, Patricia

doi:10.1111/cge.12679

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…FLNA expression normalized to GAPDH and relative to brain. b IHC from pediatric normal human bladder shows cytoplasmic and some nuclear smooth muscle expression of FLNA genetic diseases [58]. The classic OPDSDs are osteochondrodysplasias including OPD1, OPD2, frontometaphyseal dysplasia (FMD), MNS, and terminal osseous dysplasia with pigmentary defects (TOD) [42].…”

Section: Discussionmentioning

confidence: 99%

“…In 1987, prune belly sequence was observed in a MNS patient not sequenced for FLNA [73]. More recently, four males with lethal MNS and FLNA exon 22 mutations disrupting Ig10 have been described with genitourinary abnormalities including omphalocele, megacystis, and/or "prune belly-like" phenotype of abdominal wall laxity [58,74,75]. A lethal form of FMD from FLNA exon 22 mutation was noted in a male with distended abdomen, megaureters and hydronephrosis [76].…”

Section: Discussionmentioning

confidence: 99%

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Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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Background: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. Methods: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. Results: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin ) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). Conclusions: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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“…MNS is a rare X‐linked condition. The female phenotype has been well documented, but the male phenotype has been reported in molecularly confirmed instances of the condition on only three occasions (Naudion et al, ; Santos et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent publications have expanded the mutational spectrum to include additional missense variants in exon 22 (p.Gly1176Asp, p.Tyr1229Ser, and p.Val1163Leu), in exon 7 (p.Gly352Trp) as well as a deletion spanning the exon 28–intron 28 junction (Foley et al, ; Moutton et al, ; Santos et al, ). Despite additional mutations identified in other exons, the vast majority of MNS is caused by missense mutations in exon 22, and >70% of published mutations are accounted for by the two recurrent mutations (Foley et al, ; Moutton et al, ; Naudion et al, ; Parrini et al, ; Robertson et al, ; Santos et al, ). As MNS is extremely rare, no data regarding prevalence in specific populations groups have been published.…”

Section: Discussionmentioning

confidence: 99%

“…Prior to the discovery of mutations in FLNA as being causative of the condition, it was considered that two male MNS phenotypes existed, one mild presentation and a severe perinatal lethal presentation (Krajewska‐Walasek, Winkielman, Gorlin, & Reynolds, ). Since then, only four mutation‐positive males, including the present case, have been described with the condition; all exhibiting a severe phenotype (Naudion et al, ; Santos et al, ).…”

Section: Introductionmentioning

confidence: 88%

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A recurrent mutation causing Melnick‐Needles syndrome in females confers a severe, lethal phenotype in males

Spencer

Lombaard

Wise³

et al. 2018

American J of Med Genetics Pt A

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Melnick-Needles syndrome (MNS; MIM 309350) is an X-linked skeletal dysplasia caused by mutations in FLNA. Females with the condition present with characteristic facial features, short stature, skeletal anomalies, including poorly modeled and sclerotic bones, and structural abnormalities such as cardiac and urological defects. Previously males were thought to present with either a mild phenotype compatible with life or a severe lethal presentation depending on the maternal phenotype. The discovery of a limited number of mutations in FLNA as the cause of the condition has clarified the molecular basis of the disorder, but only a very small number of severely affected males have been reported with MNS. Furthermore, no mildly affected males have been described with a molecular confirmation of the condition. In this report, we describe the clinical and molecular findings of a mildly affected mother with MNS and her severely affected son. They shared a well-documented disease-causing variant in FLNA, p.(Ala1188Thr), one of two highly recurrent mutations leading to the disorder. This is only the fourth report of a male with perinatal lethal MNS and a molecular confirmation; it is the first description of this specific mutation in a male.

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Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

Wade

Jenkins

Daniel

et al. 2017

American J of Med Genetics Pt A

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Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFβ-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

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Fetal phenotypes in otopalatodigital spectrum disorders

Cited by 18 publications

References 15 publications

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

A recurrent mutation causing Melnick‐Needles syndrome in females confers a severe, lethal phenotype in males

Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

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