Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes

Bhoj, Elizabeth; Haye, Damien; Toutain, Annick; Bonneau, Dominique; Nielsen, Irene Kibæk; Lund, I. Bay; Bogaard, Pauline; Leenskjold, Stine; Karaer, Kadri; Wild, K. Taylor; Grand, Katheryn; Astiazarán, Mirena C; Gonzalez-Nieto, Luis A; Carvalho, Ana Carolina de; Lehalle, Daphné; Amudhavalli, Shivarajan; Repnikova, Elena; Saunders, Carol J.; Thiffault, Isabelle; Saadi, Irfan; Liu, Dong; Hákonarson, Hákon; Vial, Yoann; Zackai, Elaine H.; Callier, Patrick; Drunat, Séverine; Verloès, Alain

doi:10.1016/j.ejmg.2018.11.022

Cited by 27 publications

(40 citation statements)

References 38 publications

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“…Subject 6 was originally described as Family 9, Individual 9-1 by Bhoj et al (2019) The combination of hypertelorism, facial cleft, and CDH has previously been reported in rare case reports of X-linked Opitz G/BBB (OMIM #300000), caused by pathogenic variants in MID1 (Taylor & Aftimos, 2010). This combination has also been seen in other craniofacial disorders with midline defects including craniofrontonasal dysplasia (OMIM #304110) caused by pathogenic variants in EFNB1, and…”

Section: Subjectmentioning

confidence: 89%

“…(Kruszka et al, 2015). He was found to have a missense variant c.3293G>A p. Arg1098Glnin SPECC1L (Table 1) (Bhoj et al, 2019).…”

Section: Subjectmentioning

confidence: 99%

“…Subjects 4 and 5 were originally described as Individual 4-II-1 and 4-II-2 by Bhoj et al (2019). The mother of Subjects 4 and 5 was a 28-year-old woman with micrognathia, ocular hypertelorism, A c.1258G>A p.(Glu420Lys) variant in SPECC1L was found to be de novo in the mother and inherited in the two fetuses, Subjects 4 and 5 (Table 1) (Bhoj et al, 2019).…”

Section: Subjects 4 Andmentioning

confidence: 99%

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Congenital diaphragmatic hernia as a prominent feature of a SPECC1L‐related syndrome

Wild

Gordon

Bhoj

et al. 2020

American J of Med Genetics Pt A

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Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in 30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X-linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L-related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L-related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus. K E Y W O R D S congenital diaphragmatic hernia (CDH), MID1, Opitz G/BBB syndrome, SPECC1L-related syndrome 1 | INTRODUCTION Congenital diaphragmatic hernia (CDH) is a relatively common birth defect that occurs in approximately 1 in 2,500 live births (Langham, Kays, Ledbetter, et al., 1996). CDHs are associated with substantial morbidity and mortality related to the degree of pulmonary hypoplasia, size of diaphragmatic defect, pulmonary hypertension, and associated anomalies (Kardon, Ackerman, Mcculley, et al., 2017; Lally et al., 2007; Rygl et al., 2007). Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified K. Taylor Wild and Tia Gordon authors contributed equally to this study.

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Section: Subjectmentioning

confidence: 89%

“…(Kruszka et al, 2015). He was found to have a missense variant c.3293G>A p. Arg1098Glnin SPECC1L (Table 1) (Bhoj et al, 2019).…”

Section: Subjectmentioning

confidence: 99%

Section: Subjects 4 Andmentioning

confidence: 99%

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Congenital diaphragmatic hernia as a prominent feature of a SPECC1L‐related syndrome

Wild

Gordon

Bhoj

et al. 2020

American J of Med Genetics Pt A

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“…SCL/P follows Mendelian inheritance with disease-causing genes including IRF6 , TP63 , TBX1 , and SPECC1L [ 5 – 8 ]. In contrast, NSCL/P is thought to have a complex etiology, with genetic factors acting in concert with environmental effects, which leads to variable phenotypes and incomplete penetrance [ 3 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

Tang

Xiao

Wang

et al. 2020

BioMed Research International

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Background. Cleft lip with or without cleft palate (CL/P) is the most common facial birth defect, with a worldwide incidence of 1 in 700-1000 live births. CL/P can be divided into syndromic CL/P (SCL/P) and nonsyndromic CL/P (NSCL/P). Genetic factors are an important component to the etiology of NSCL/P. ARHGAP29, one of the NSCL/P disease-causing genes, mediates the cyclical regulation of small GTP binding proteins such as RhoA and plays an essential role in cellular shape, proliferation, and craniofacial development. Methods. The present study investigated a Chinese family with NSCL/P and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatic analysis and prediction of variant pathogenicity. Cosegregation was subsequently conducted. Results. We identified a novel heterozygous missense variant of ARHGAP29 (c.2615C > T, p.A872V) in a Chinese pedigree with NSCL/P. Conclusion. We detected the disease-causing variant in this NSCL/P family. Our identification expands the genetic spectrum of ARHGAP29 and contributes to novel approaches to the genetic diagnosis and counseling of CL/P families.

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“…SPECC1L is a cytoskeletal protein that associates with both filamentous actin and microtubules (Saadi et al 2011). Mutations in SPECC1L have been identified in multiple patients with craniofacial malformations, including cleft palate (Bhoj et al 2018;Bhoj et al 2015;Kruszka et al 2015;Saadi et al 2011). Mouse embryos homozygous for a null Specc1l gene-trap allele die between E9.5-E10.5 with open neural-folds and defects in cranial neural crest cell delamination (Wilson et al 2016).…”

Section: Introductionmentioning

confidence: 99%

SPECC1L-deficient palate mesenchyme cells show speed and directionality defect

Goering

Isai

Hall

et al. 2019

Preprint

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Clefts of the lip and/or palate (CL/P) are common anomalies that occur in 1/800 live births. Pathogenic SPECC1L variants identified in patients with rare atypical clefts and syndromic CL/P suggest the gene plays a primary role in face and palate development. We have generated Specc1l gene-trap (Specc1l cGT ) and truncation (Specc1l DC510 ) alleles that cause embryonic or perinatal lethality, respectively.Specc1l cGT/DC510 compound mutants show delayed and abnormal palatal shelf elevation at E14.5. By E15.5, the mutant shelves do elevate and fuse, however, the palatal rugae form abnormally. Palatogenesis requires extensive mesenchymal remodeling, especially during palatal shelf elevation. We posit that this remodeling involves collective movement of neural crest-derived palatal mesenchyme cells. Live time-lapse microscopy was performed to visualize in vitro wound-repair assays with wildtype and SPECC1L-deficient primary mouse embryonic palatal mesenchyme (MEPM) cells. SPECC1L-deficient MEPM cells consistently showed delayed closure in wound-repair assays. To evaluate which features of cellular movement were responsible, we performed automated particle image velocimetry (PIV) and manual cell tracking. The analyses revealed that both cell speed and directionality are disrupted in SPECC1L-deficient cells compared to controls.To determine if primary MEPM cells can move collectively, we assayed stream formation, which is a hallmark of collective movement. Indeed, MEPM cultures displayed correlated movement of neighboring cells. Importantly, correlation length was reduced in SPECC1Ldeficient cultures, consistent with a role for SPECC1L in collective migration.Furthermore, we demonstrated that activation of the PI3K-AKT pathway with the 740Y-P small molecule can rescue the wound-closure delay in SPECC1L-deficient MEPM cells. 3Cell tracking analyses showed that this rescue was due to both increased speed and improved directionality. Altogether, our data showed a novel role for SPECC1L in guided movement through modulation of PI3K-AKT signaling.

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Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes

Cited by 27 publications

References 38 publications

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L‐related syndrome

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L‐related syndrome

Identification of a Novel Variant of ARHGAP29 in a Chinese Family with Nonsyndromic Cleft Lip and Palate

SPECC1L-deficient palate mesenchyme cells show speed and directionality defect

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