Variants involving TBX4 are associated with ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS; also known as small patella syndrome), pulmonary arterial hypertension (PAH), and lethal lung developmental disorders. The variability of penetrance and expressivity of TBX4 variants remains a prominent challenge in understanding their genotype–phenotype correlations. We investigated a five‐generation family with 12 affected individuals presenting with isolated ICPPS, lung‐related manifestations with features of ICPPS, and other milder abnormalities. Whole‐genome sequencing was used to identify the causative and putative modifying variants. Wefound a complex genomic rearrangement (CGR) involving the TBX4 promoter and its 5 ′ untranslated region that segregated in the family. This CGR consists of an ~38 bp insertion, an ~24 bp deletion, an ~2.4 kb deletion, and an ~235 bp inversion. Computational analyses in the proband′s mother with pulmonary and skeletal manifestations revealed 27 candidate modifying noncoding SNVs in the TBX4 lung‐specific super‐enhancer and 45 SNVs within its topologically associating domain (TAD), including seven variants within the TBX4 promoter. To explain the variable expressivity of this CGR, we propose that one or more of the variants within the TBX4 lung‐specific super‐enhancer or TAD may act in trans with the pathogenic CGR, modulating TBX4 expression from the intact allele.
Shruti Pande, Hiuling Chan Joiner, P. Szafranski et al.· Human Mutation· 0 citations
OBJECTIVE & DESIGN
Congenital Hypopituitarism (CH) is a complex developmental disorder characterized by variable pituitary dysfunction that is often associated with midline structural abnormalities that affect the brain, eyes and face. To date, only ∼10-15% of patients have an underlying molecular basis.
METHODS
Next generation sequencing was conducted on a subset of CH patients with no known genetic aetiology. Human embryonic brain tissue sections were used to generate an expression profile, and a knock-out mouse model was generated using CRISPR-Cas9 gene editing and phenotypically analysed.
RESULTS
Two novel homozygous frameshifts in CCDC149, p.Gly278* and p.Leu222*, were identified in two unrelated CH pedigrees (three patients), respectively. Patient phenotypes included growth hormone deficiency (GHD), hypogonadotropic hypogonadism, and developmental delay/autism. Severe scoliosis was present in one pedigree, with a small anterior pituitary on MRI in the other. Human embryonic CCDC149 was localised to the developing hypothalamo-pituitary region at Carnegie stages 16-23, and Ccdc149-null mice recapitulated patient phenotypes, including growth impairment and reduced fertility compared to wild-type littermates.
CONCLUSIONS
Our study is the first to report CCDC149 variants in association with CH. Previous studies in C.elegans report CCDC149 orthologue expression in the basal bodies of ciliated neurons, supporting the possibility of impaired ciliary function as an underlying mechanism in this complex disorder.
L. Gregory, Shoshana Rath, Hanna Mandel et al.· European Journal of Endocrin...· 0 citations