Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities

Klinicko-geneticky pristup ku skeletalnym dysplaziam s osobitym zameranim na skeletalne dysplazie podmienene mutaciami FGFR3 genu.

We have investigated a large group of 217 patients with skeletal dysplasias from almost all regions of Czech and Slovac Republics. I personally performed clinical-genetic investigations in 142 patients of the group. In 75 cases the diagnosis has been established with the help of photographic documentation and X-rays, and eventually by means of molecular biology. The most frequently encountered skeletal dysplasias within our group were those changes in the FGFR3 gene (achondroplasia, thanatophoric dysplasia, hypochondroplasia). The most frequently occuring skeletal dysplasia from our group of patients was achondroplasia (62 patients, predominantly children). Out of those, 4 patients presented with familiar achondroplasia and 58 with sporadically occuring achondroplasia. Achondroplasia can be diagnosed very soon, actually in the neonatal period. 52 patients of achondroplasia underwent the FGFR3 gene evaluation, and we found Gly380Arg mutation of the FGFR3 gene in 48 (i.e. 92%) of them. Such a high finding of the mutation proves the clinical homogeneity of this most frequently occuring dysplasia and as in favour of a reliable clinical diagnosis procedure. The most frequently occuring lethal skeletal dysplasia, the thanatophoric dysplasia, is diagnosed with a lesser sensitivity. Various rare lethal forms of skeletal dysplasias are erroneously diagnosed as thanatophoric dysplasia. The principal source of errors when establishing the diagnosis of thanatophoric dysplasia is the low gestational age of the foetus. In such cases, a great experience is necessary to assess the prenatal ultrasonography with consecutive evaluation of the X-ray picture and the phenotype of the foetus after the termination of the pregnancy. In our group we have 15 cases of thanatophoruic dysplasia diagnosed pre- and postnatally. In 13 cases (87%) we have found the FGFR gene mutations. In contrast to achondroplasia and thanatophoric dysplasia the diagnosis of hypochondroplasia remains the least certain. The principal reason is the apparent genetic heterogeneity of hypochondroplasia and the absence of specific clinical and radiological changes. We performed the molecular diagnosis in 69 patients (mostly children) with suspected hypochondroplasia. In most of the patients, there was no accompanying documentation, or the radiologic documentation was incomplete. In only 10 cases (13%) we have confirmed the molecular diagnosis of hypochondroplasia. The children with confirmed mutation (Asn540Lys) had a phenotype similar to that of a "grown" achondroplasia and clinically they were almost interchangeable with achondroplasia. In our group of 217 patients we have diagnosed several rare skeletal dysplasias. In two cases there were new, previously not yet described dysplasias of an unknown aetiology. These have been entered into the world syndromologic programme POSSUM/OSSUM as new types of skeletal dysplasias, termed as "Rhizo-mesomelic bone dysplasia -Bratislava type" and "Spondylometaphyseal dysplasia - Bratislava type". In cases of rare skeletal dysplasias, the same as in the cases of FGFR3 mutations-induced dysplasias, we have documented case reports at the scientific level required by the world syndromologic programs (POSSUM/OSSUM, London Dysmorphology) and we have contributed to the image data of these programs. The image data (X-rays, photographs) are implemented in both the pre- and postgradual education within our faculty. The diagnosis of skeletal dysplasias requires substantial experience when evaluating the radiograms and the phenotype of the patient. The experience of the relevant specialist (paediatrician, genetician, radiologist) increases with the number of correctly diagnosed skeletal dysplasias. Only highly specialised centers focused on the diagnosis and therapy of skeletal dysplasias can meet such criteria. This is the only way how to achieve early and correct diagnosis and therapy in such patients.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi