Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders.

Recent studies suggest that copy number variations (CNVs) encompassing several genes involved in neurodevelopmental pathways are associated with a variety of neuropsychiatric phenotypes, including developmental delay (DD), mental retardation (MR), and autism spectrum disorders (ASDs). Here we present eight patients in a cohort of approximately 1,200 patients referred for clinical array CGH testing for various neurodevelopmental phenotypes,whowere identified to carry small (<1.0Mb with the majority <500 kb) either total gene or intragenic deletions encompassing critical synaptic and other neurodevelopmental genes. The presentations of these patients included variable degrees of DD, speech problems, learning disabilities, MR, autistic-like features, and mild non-specific dysmorphic features. These genes belong to four functional categories, including neuronal transcription factor genes (NFIA at 1p31.3, MEF2C at 5q14.3, andCAMAT1at 1p36.23p36.31), neuron-specific splicing factor genes (RBFOX1 at 16p13.2p13.3), genes involved in synapse formation and maintenance (CNTNAP2 at 7q35 and LRFN5 at 14q21.2), and genes involved in neurotransmission (CHRNA7 at 15q13.3 and IL1RAPL1 at Xp21.2p21.3). Our report expands the list of neurodevelopmental genes deleted in various neurobehavioral phenotypes, expands the phenotypes caused by haploinsufficiency of previously reported critical neurodevelopmental genes, and elucidates the clinical relevance and need for careful clinical interpretation of some small CNVs<500 kb. This report also suggests that small clinically relevant deletions encompassing critical synaptic and other neurodevelopmental genes can present clinically with various neurobehavioral phenotypes, which implies the existence of overlapping neuronal pathways in the pathogenesis of these phenotypes.

IRF6 mutations in mixed isolated familial clefting.

Mutations in the interferon regulatory factor 6 (IRF6) gene are known to cause van der Woude syndrome (VWS), a common syndromic form of oro-facial clefting characterized by the familial occurrence of mixed clefting (cleft lip with or without a cleft palate and cleft palate alone in the same family) and lower lip pits. As lip pits are not present in all cases of VWS, IRF6 mutations can cause a phenotype identical to non-syndromic clefting. However, recent studies failed to identify IRF6 mutations in sporadic and familial non-syndromic clefting, concluding that testing for IRF6 was not warranted for sporadic or familial non-syndromic clefting. Here we report on two families that demonstrate familial mixed clefting in which mutations in IRF6 were identified, suggesting that IRF6 testing does have a role in familial, non-syndromic OFC.

Further delineation of the Kapur-Toriello syndrome.

The Kapur-Toriello syndrome (KTS) is a rare multiple congenital anomaly syndrome, with presumed autosomal recessive inheritance based on the initial report of affected siblings. Here we report on a female with multiple anomalies, including cleft lip and palate, coloboma, mental retardation with cerebral atrophy, and imperforate anus who, upon re-evaluation at 30 months, was recognized to have a columella that extended below the nares. This distinctive finding prompted the diagnosis of KTS. This is the 5th report of KTS, and the second female. Interestingly, both female cases also manifest an ano/rectal malformation, suggesting that this should be considered a component manifestation of this rare syndrome.

Imperforate anus is a rare associated finding in blepharocheilodontic syndrome.

Blepharocheilodontic (BCD) syndrome is a rare autosomal-dominant condition that is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. It exhibits considerable phenotypic variability among affected individuals. An additional rare associated manifestation is imperforate a.u. (IA), which has been reported in three cases [Guyuron et al. (1995); J Craniofac Surg 6:392-394; Gorlin et al. (1996); Am J Med Genet 65:109-112; da Silva Lopes et al. (2003); Am J Med Genet Part A 121A:266-270]. Here we report on a family with BCD that includes IA, confirming that anorectal anomalies are a part of BCD syndrome.