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. Graphic Abstract: [Figure not available: see fulltext.

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

Genetic population structure, gene flow, and evolutionary history of selected ornamental fish in the Red Sea

The ornamental fishery is expanding rapidly in the Red Sea, and concerns about the possibility of overexploitation were raised. Marine protected areas (MPAs) were addressed as a potential solution to prevent overexploitation. However, the sources of stock recruitment are not well understood. This thesis aims to reveal the genetic population structure and the demographic connectivity in the endemic fish species of the Red Sea Larabicus quadrilineatus, and in the two common fish species Chromis viridis and Pseudanthias squamipinnis. The fish samples were obtained from five locations in the Red Sea. For comparison, additional samples of the two common species were obtained from two locations in the Indo-Malay Archipelago. Partial sequence of the mitochondrial control region was used as a molecular marker in the three studied species. The studied species exhibited high genetic diversity as inferred from the haplotype and nucleotide indices. Analysis of molecular variance (AMOVA) detected significant genetic variation between northern and central/southern populations of L. quadrilineatus (ΦCT = 0.01; P < 0.01), and between the populations in the Gulf of Aqaba and the Red Sea proper of P. squamipinnis (ΦST = 0.02; P < 0.01). In addition, AMOVA detected significant genetic variation between the Red Sea and the Indo-Malay Archipelago for both C. viridis (ΦCT = 0.462; P < 0.001) and P. squamipinnis (ΦST = 0.78; P < 0.001). Migration analysis in the Red Sea revealed (1) higher migration into the Gulf of Aqaba for all species; (2) higher northward migration for C. viridis and L. quadrilineatus; and higher southward migration in the Red Sea proper for P. squamipinnis. A significant relationship between the genetic versus the geographic distances was shown only for L. quadrilineatus, and as a consequence the mean larval dispersal distance based on the isolation-by-distance model was estimated to be between 0.44 and 5 km. Estimates of the effective population size were the highest (1) in Hodeidah (southern Red Sea) for both L. quadrilineatus and C. viridis; and (2) in Tor (northern Red Sea) for P. squamipinnis. The results in this thesis were discussed in relation to the oceanographic factors and the biological features of the studied fishes. The historical event Last Glacial Maximum proved its influence on the population demographic history and the currents effective population size of the studied species. In order to enable a sustainable ornamental fishery on the studied species in the Red Sea, the results of this thesis suggest that (1) populations in the Red Sea should be managed as one stock for C. viridis; (2) populations of L. quadrilineatus northern and southern Red Sea should be managed as two stocks; and (3) populations in the Gulf of Aqaba and in the Red Sea proper should be managed separately for P. squamipinnis. The rather low larval dispersal distance of about 5 km needs to be considered in the design of MPAs to enable connectivity and self-seeding in L. quadrilineatus

First Record Mutations in the Genes ASPA and ARSA Causing Leukodystrophy in Jordan

Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan

Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype

TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygousTAF1Cmissense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant ofUBTF, which encodes another transcription factor of Pol I.TAF1Cvariants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts,TAF1CmRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairingTAF1Cexpression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating theTAF1Cmissense variants with a severe neurological phenotype for the first time.Peer reviewe

Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi‐allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD‐EU register database and an in‐house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi‐allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features