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Review
. 2023 Sep 29;96(3):383-396.
doi: 10.59249/UTCP9818. eCollection 2023 Sep.

A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family

Hamna Shahid  1 , Nazish Shakoor  2 , Anisa Bibi  2 , Asma Saleem Qazi  1 , Rida Fatima Saeed  1 , Aqeela Nawaz  2 , Sajid Malik  2 , Sara Mumtaz  1
Affiliations
Review

A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family

Hamna Shahid et al. Yale J Biol Med. .

Abstract

Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.

Keywords: carpal and tarsal fusion; coxa valga; kyphoscoliosis; lordosis; pectus carinatum; short stature; winged scapula.

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Figures

Figure 1
Figure 1
A. Pedigree of the family. Horizontal lines above individuals indicate that physical examination was performed. *indicates subjects participated in genetic study; “E,” subjects underwent WES. B. Phenotype in affected subjects 405 and 407. C. Roentgenographic examination of 405. D. Electropherograms showing the segregation of identified variant c.220C>T in FLNB.
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