We report the identification of a recurrent 520-kbp 16p12.1 microdeletion significantly associated with childhood developmental delay. The microdeletion was detected in 20/11,873 cases vs. 2/8,540 controls (p=0.0009, OR=7.2) and replicated in a second series of 22/9,254 cases vs. 6/6,299 controls (p=0.028, OR=2.5). Most deletions were inherited with carrier parents likely to manifest neuropsychiatric phenotypes (p=0.037, OR=6). Probands were more likely to carry an additional large CNV when compared to matched controls (10/42 cases, p=5.7×10-5, OR=6.65). Clinical features of cases with two mutations were distinct from and/or more severe than clinical features of patients carrying only the co-occurring mutation. Our data suggest a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity suggests that this two-hit model may be more generally applicable to neuropsychiatric disease.

A hypothesis is presented to explain the pathogenesis of the Poland, Klippel-Feil, and Möbius anomalies, isolated absence of the pectoralis major with breast hypoplasia, isolated terminal transverse limb defects, and the Sprengel anomaly. We propose that these conditions are the result of an interruption of the early embryonic blood supply in the subclavian arteries, the vertebral arteries and/or their branches, and hypothesize that the occlusions occur at specific locations in these vessels during or around the sixth week of embryologic development and produce predictable patterns of defects. The term subclavian artery supply disruption sequence (SASDS) is suggested for the group of birth defects represented by the above conditions. Possible causes for interruption of embryonic blood supply are discussed.

The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia. Twenty-two cases of WBS were examined clinically and cytogenetically, and compared to 226 previously reported cases. Aspects of the clinical evaluations are discussed. All individuals examined were chromosomally normal with no evidence of 11p abnormality as has been reported recently. The relevance of a possible relationship between clinical findings, chromosome abnormalities, and genes present on 11p is discussed. Transmission of this condition is most consistent with autosomal dominant inheritance with incomplete penetrance.

We used trio-based whole-exome sequencing to analyze two families affected by Weaver syndrome, including one of the original families reported in 1974. Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected proband identified a third de novo mutation in this gene. These data show that mutations in EZH2 cause Weaver syndrome.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

We have identi®ed 25 cases with what we are calling the partial urorectal septum malformation (URSM) sequence, which were seen in our institution over the past 27 years. The partial URSM sequence is de®ned as a single perineal/anal opening that drains a common cloaca in combination with an absent (imperforate) anus. In the 25 patients reported here, the partial URSM sequence was more common in females, with a female to male ratio of 18 to 7. Ambiguous genitalia were common in both sexes. Internal pelvic structures typically showed a cloaca with the bladder and rectum (and vagina in females) coalescing into a common canal that connected to the external surface in the perineal or anal area. Abnormalities of the internal genitalia were also common, with 12 females having a bi®d or septate vagina and 11 having a bicornuate uterus. Renal anomalies were frequent in both sexes, with 10 of 25 patients having unilateral cystic renal dysplasia and 7 of 25 patients having unilateral renal agenesis. Twenty-one of 25 patients survived long term. By de®nition, the partial URSM sequence is a milder expression of the full URSM sequence, which is de®ned as having no perineal or anal openings and is typically associated with an internal cloaca. The URSM spectrum, which encompasses the partial and full URSM sequences, is believed to be caused by abnormalities of septation of the primitive cloaca. The URSM spectrum is distinct from the VATER association and conditions caused by sex hormone abnormalities, such as congenital adrenal hyperplasia. ß

We report 281 individuals carrying a pathogenic recurrent NF1

(7Med Genet 1998;35:420-424)