Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.

Approximately 3% of the live-born infants have major dysmorphic features, and about two-thirds of which are observed in the maxillofacial region; however, in many cases, the etiology of the dysmorphic features remains uncertain. Recently, the genome-wide screening of large patient cohorts with congenital disorders has made it possible to discover genomic aberrations corresponding to the pathogenesis. In our analyses of more than 536 cases of clinically undiagnosed multiple congenital anomalies and mental retardation (MR) by microarray-based comparative genomic hybridization, we detected two non-consanguineous unrelated patients with microdeletions at 10p11.23-p12.1, which overlapped for 957 kb, including four protein-coding genes: ARMC4, MPP7, WAC and BAMBI. As the two patients had similar phenotypes; for example, MR and multiple maxillofacial abnormalities including midface retrusion, wide mouth and large tongue, we assessed the phenotypes in detail to define the common features, using quantitative evaluations of the maxillofacial dysmorphism. The concordance of the genetic and phenotypic alterations is a good evidence of a new syndrome. Although an interstitial deletion of 10p is rare, the current study is the first trial to examine precisely the craniofacial characteristics of patients with a heterozygous deletion at 10p11.23-p12.1, and presents good evidence to diagnose potential patients with the same genetic cause.

Axenfeld-Rieger anomaly and Axenfeld-Rieger syndrome: clinical, molecular-cytogenetic, and DNA array analyses of three patients with chromosomal defects at 6p25.

Clinical phenotypes of and genetic aberrations in three unrelated Japanese patients with Axenfeld-Rieger anomalies and various accompanying malformations of systemic organs are described. GTG-banded chromosome analysis showed terminal deletions of the short arm of chromosome 6 in two patients and an inversion, inv(6)(p25q14), in the other. FISH and DNA array analyses revealed that the two patients with deletions had 5.0-5.7 Mb and 6.6 Mb 6p terminal deletions, respectively, and FOXC1 was apparently deleted in both patients. In the other patient, the inversion breakpoint at 6p25 was estimated to be in or very close to the FOXC1 locus, but DNA array analysis did not reveal a deletion around the breakpoint. Common extraocular findings in these patients included broad forehead, brachycephaly, hypertelorism, downslanting palpebral fissures, small anteverted nose, and cardiac defects. Two patients also exhibited autistic characteristics. The two patients with deletions exhibited poor muscle tone and developmental delays. Most of these extraocular findings were similar to those found in previous patients with FOXC1 mutations and distinct from those found in patients with PITX2 mutations, who frequently develop umbilical and dental anomalies. We suggest that the psychomotor retardation is a clinical manifestation associated with a deletion of multiple contiguous genes in the 6p terminus and that this phenomenon is similar to the 6p25 deletion syndrome. Understanding the relationship between genetic lesions and the spectrum of extraocular findings in patients with Axenfeld-Rieger anomalies may lead to better clinical management.

Microdeletion of the Down syndrome critical region at 21q22.

The concept of the Down syndrome critical region implies the existence of several dosage-sensitive genes that result in an abnormal phenotype when duplicated. Among the genes in the presumed Down syndrome critical region, DYRK1A and SIM2 are thought to be particularly important because of their critical roles in the development of the central nervous system in model organisms. Considering that regulatory imbalances resulting in an altered amount of expression from crucial target genes tend to produce phenotypic effects in both monosomics and trisomics, haploinsufficiency for the Down syndrome critical region is expected to be associated with an abnormal phenotype. We report on a patient with severe microcephaly, a developmental delay, hypospadias, and corneal opacity who had a microdeletion spanning the Down syndrome critical region, including DYRK1A and SIM2. He presented with intrauterine growth retardation, hypospadias, corneal clouding, arched eyebrows, upslanting and narrow palpebral fissures, bifid uvula, prominent nasal root, short columella, prominent central incisors, pegged shaped teeth, retrognathia, hypoplastic nipples, and severe developmental delay. His G-banded karyotype was normal, but array comparative genomic hybridization showed a de novo deletion of 3.97 Mb at chromosome 21q22. The extreme degree of microcephaly in this patient may be ascribed to the haploinsufficiency of DYRK1A, since brain size is severely reduced in heterozygotes for the Dyrk1a null mutation in mice.

Neocentromere marker chromosome of distal 3q mimicking dup(3q) syndrome phenotype.

Supernumerary marker chromosomes (SMCs) lacking alpha-satellite sequences and possessing a newly derived functional centromere are referred to as neocentromere marker chromosomes (NMCs). Although the delineation of the chromosome content of these NMCs would be helpful for genetic counseling, such fine mapping has been difficult because of the limited sizes of the involved segments. We report on a female patient with mosaic NMC involving 3q26.3-3qter, the content of which was determined using an array CGH analysis. Our results support the validity of an array CGH-based approach to investigating the origins of SMCs. Further FISH analyses revealed that the NMC is characterized by an asymmetric inv-dup structure separated by a single-copy region. The present case had many manifestations of dup(3q) syndrome, the critical interval of which is considered to be 3q26.3-q27. Common features included mental and growth retardation, hirsutism, synophrys, a broad nasal root, anteverted nares, downturned corners of the mouth, and malformed ears. The observation gives further credence to the concept that the critical region responsible for the dup(3q) phenotype to 3q26.3-q27.

Redefining the phenotypic spectrum of de novo heterozygous CDK13 variants: Three patients without cardiac defects.

Recently, 7 patients with de novo constitutional non-synonymous mutations in the CDK13 gene were ascertained through a trio exome analysis of a large cohort of 610 patients with congenital cardiac diseases. Despite another report describing 9 additional patients, the clinical spectrum of this condition has yet to be defined. Herein, we report 3 patients with heterozygous constitutional CDK13 mutations, who were ascertained through exome analysis of children with intellectual disability and minor anomalies, who lacked cardiac anomalies. Two patients had a c.2149G > A, p.Gly717Arg mutation, and one had a c.2525A > G, p. Asn842Ser mutation. A review of the previously described patients and those described herein has enabled the following points to be clarified. First, congenital heart diseases are not an essential feature (13/19). Second, nasal features may help syndromic recognition (14/16). Third, widely spaced and peg-shaped teeth may represent a previously unappreciated diagnostic clue for this newly identified syndrome. Here, we show that p.Gly717Arg represents a hotspot in addition to p.Asn842Ser. We suggest that this CDK13-related disorder may represent a clinically recognizable syndrome.

Taste after reduction of the tongue in Beckwith-Wiedemann syndrome.

We tested the sensitivity of taste after reduction of the tongue in four girls with Beckwith-Wiedemann syndrome. No patient had taste blindness, but the ability to detect salty and bitter tastes declined after reduction of the tongue.

Wide phenotypic variations within a family with SALL1 mutations: Isolated external ear abnormalities to Goldenhar syndrome.

We report on wide phenotypic variations within a family with SALL1 mutations; the elder sister presented with a Townes-Brocks syndrome phenotype including external ear anomalies, preaxial polydactyly, and anteriorly placed anus, whereas the younger sister presented with a phenotype resembling Goldenhar syndrome, including atretic ear canals, mandibular hypoplasia, and right preaxial polydactyly as well as an epibulbar dermoid. The mother had abnormal external ears but was otherwise structurally normal, and the father was asymptomatic. Analysis of the SALL1 gene revealed that both daughters were heterozygous for nonsense mutation 1256T>A (L419X), that is present 5' to the region encoding the first double zinc finger. The mother was heterozygous for the L419X mutation. The younger daughter is the first patient with a SALL1 mutation to exhibit a classic Goldenhar syndrome-like phenotype with an epibulbar dermoid. The observation lends further support to the concept that Goldenhar syndrome is an etiologically heterogeneous disorder that may have a genetic basis in some cases.