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

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.

Consanguinity, inbreeding coefficient, fertility and birth-outcome in population of Okara district, Pakistan.

OBJECTIVES: This study was aimed to illustrate the determents of consanguinity and inbreeding coefficient-F (ICF) in the population of Okara district of Pakistan and to elucidate the impact of consanguinity on fertility and birth outcome. METHODS: Through a cross-sectional sampling design, 1,521 married women were recruited from Okara district during 2016-2017. Data on demographic variables, marital union types, subject's fertility, and reproductive outcome, were gathered in face-to-face interviews. Descriptive statistics and multivariable logistic regression were employed. RESULTS: The prevalence of consanguineous unions (CU) was calculated to be 61% yielding ICF=0.0356. Multivariable regression analyses revealed that six variables including younger age at marriage, joint family structure, caste-system of spouse, exchange marriage, matrimonial distance, and parental consanguinity, were significant predictors of consanguinity. The women having CU had significantly higher mean fertility, mean live-births and mean live-born sons compared with subjects having non-consanguineous unions (NCU). However, there were no significant differences in the average mortalities, i.e., prenatal, postnatal and <5 years, between the mothers with CU and NCU. CONCLUSION: The prevalence of consanguineous unions (CU) in Okara district is quite high like other inbred populations of Pakistan. The striking findings of this study are the higher mean fertility and mean live-births in women with CU. The likely reasons underlying this phenomenon have been discussed.