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Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non-mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range.

ABSTRACT Copy number gains at Xq28 are a frequent cause of X-linked intellectual disability ( XLID). Here, we report on a recurrent 0.5 Mb tandem copy number gain at distal Xq28 not including MECP2, in four male patients with nonsyndromic mild ID and behavioral problems. The genomic region is duplicated in two families and triplicated in a third reflected by more distinctive clinical features. The X-inactivation patterns in carrier females correspond well with their clinical symptoms. Our mapping data confirm that this recurrent gain is likely mediated by nonallelic homologous recombination between two directly oriented Int22h repeats. The affected region harbors eight genes of which RAB39 B encoding a small GTPase, was the prime candidate since loss-of-function mutations had been linked to ID. RAB39 B is expressed at stable levels in lymphocytes from control individuals, suggesting a tight regulation. m RNA levels in our patients were almost two-fold increased. Overexpression of Rab39b in mouse primary hippocampal neurons demonstrated a significant decrease in neuronal branching as well as in the number of synapses when compared with the control neurons. Taken together, we provide evidence that the increased dosage of RAB39 B causes a disturbed neuronal development leading to cognitive impairment in patients with this recurrent copy number gain. [ABSTRACT FROM AUTHOR]

Background Alport syndrome (AS), a hereditary type IV collagen nephropathy, is a major cause of end-stage renal disease in young people. About 85% of the cases are X-linked (ATS), due to mutations in the COL4A5 gene. Rarely, families have a contiguous gene deletion comprising at least exon 1 of COL4A5 and the first exons of COL4A6, associated with the development of diffuse leiomyomatosis (ATS-DL). We report three novel deletions identified in families with AS, one of which challenges the current concepts on genotype-phenotype correlations of ATS/ATS-DL. Methods In the setting of a multicentric study aiming to describe the genetic epidemiology and molecular pathology of AS in Portugal, three novel COL4A5 deletions were identified in two families with x-linked Alport syndrome (ATS) and in one family with ATS-DL. These mutations were initially detected by PCR and Multiplex Ligation-dependent Probe Amplification, and further mapped by high-resolution X chromosomespecific oligo-array and PCR. Results In the ATS-DL family, a COL4A5 deletion spanning exons 2 through 51, extending distally beyond COL4A5 but proximally not into COL4A6, segregated with the disease phenotype. A COL4A5 deletion encompassing exons 2 through 29 was identified in one of the ATS families. In the second ATS family, a deletion of exon 13 of COL4A5 through exon 3 of COL4A6 was detected. Conclusions These observations suggest that deletion of the 50 exons of COL4A6 and of the common promoter of the COL4A5 and COL4A6 genes is not essential for the development of leiomyomatosis in patients with ATS, and that COL4A5_COL4A6 deletions extending into COL4A6 exon 3 may not result in ATS-DL. [ABSTRACT FROM AUTHOR]