Siblings with profound connective tissue disease: First report of biallelic TGFBR1-related Loeys-Dietz syndrome.

Heterozygous missense variants in TGFBR1, encoding one subunit of the transforming growth factor-beta receptor, are a well-established cause of Loeys-Dietz syndrome (LDS)-an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life-threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of TGFBR1-related disease. Each born at 38 weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66 days of age and Patient 2 is alive at 4 years and 4 months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF-ß responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of TGFBR1 (c.239G>A; p.Arg80Gln paternal and c.313C>G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS-an established autosomal dominant disease. These siblings represent the first reports of biallelic TGFBR1-related LDS and expand the differential diagnosis of CDH.

Biallelic GTF2IRD1 variants in brothers with profound neurodevelopmental disorder: A possible novel disorder involving a critical gene for Williams syndrome.

GTF2IRD1, a gene on chromosome 7 which encodes a transcription factor, is of significant clinical interest due to its heterozygous loss as part of the classical deletion associated with Williams-Beuren syndrome (WBS). However, biallelic variants in GTF2IRD1 alone as part of an autosomal recessive disease have not been previously reported. Here, we present two full brothers with variants in trans of GTF2IRD1 at c.1231C > T (p.Arg411Trp) and c.2632C > G (p.Leu878Val). A detailed clinical phenotype is described, which includes severe neurodevelopmental disability, facial dysmorphology, and pectus excavatum. Importantly, out of eight full siblings, only these two brothers harboring both variants in trans present with the profound described phenotype. We present the possibility that these brothers represent the identification of a new syndrome characterized by biallelic variants in GTF2IRD1, which may also have important implications for the molecular etiology of WBS.