Robert F. Stratton

Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly

Abstract. Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. The genetic causes of HPE have recently begun to be identified, and we have previously shown that HPE can be caused by haploinsufficiency for SONIC HEDGEHOG (SHH). We hypothesize that mutations in genes encoding other components of the SHH signaling pathway could also be associated with HPE. PATCHED-1 (PTCH), the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. We analyzed PTCH as a candidate gene for HPE. Four different mutations in PTCH were detected in five unrelated affected individuals. We predict that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations cause decreased SHH signaling, and HPE results. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. These findings further demonstrate the genetic heterogeneity associated with HPE, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical condition.

Miller-Dieker syndrome: Lissencephaly andmonosomy 17p

Miller-Dieker syndrome, which includes lissencephaly and a characteristic phenotypic appearance, has been reported to have an autosomal recessive pattern of inheritance. However, we have found abnormalities of chromosome 17 in two of three unrelated patients with this syndrome, one with a ring chromosome 17 and the other with an unbalanced translocation resulting in partial monosomy of 17p13. A review of the literature revealed five additional patients in three families, who had Miller-Dieker syndrome and an abnormality of 17p. Thus, we propose that monosomy of distal 17p may be the cause of Miller-Dieker syndrome in some patients.

Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q.

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280–286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located. Am. J. Med. Genet. 85:455–462, 1999.

New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13

SummaryThe Miller-Dieker Syndrome (MDS) consists of lissencephaly, characteristic facies, pre- and postnatal growth retardation, plus various other birth defects. Autosomal recessive inheritance has been presumed based on four reported families with two or more affected siblings. We present substantial evidence that monosomy 17p13.3 causes the MDS phenotype. This includes two patients with ring chromosome 17, one patient with a de novo 17p13 deletion, and one patient with monosomy 17p due to an unbalanced 7p; 17p translocation. We report the first prenatal diagnosis of MDS in a 20-week fetus from this latter family. Additionally, we report a balanced translocation between chromosome 17 and different autosomes (8, 12, and 15) in three of the four familial cases of lissencephaly. The finding of a chromosomal basis for this presumed autosomal recessive disorder significantly alters genetic counseling and makes prenatal diagnosis possible in some families.

Original articleMiller-Dieker syndrome: Lissencephaly andmonosomy 17p1

Miller-Dieker syndrome, which includes lissencephaly and a characteristic phenotypic appearance, has been reported to have an autosomal recessive pattern of inheritance. However, we have found abnormalities of chromosome 17 in two of three unrelated patients with this syndrome, one with a ring chromosome 17 and the other with an unbalanced translocation resulting in partial monosomy of 17p13. A review of the literature revealed five additional patients in three families, who had Miller-Dieker syndrome and an abnormality of 17p. Thus, we propose that monosomy of distal 17p may be the cause of Miller-Dieker syndrome in some patients.

Chromosomal microarray analysis (CMA) detects a large X chromosome deletion including FMR1, FMR2, and IDS in a female patient with mental retardation†‡

Chromosomal microarray analysis (CMA) by array‐based comparative genomic hybridization (CGH) is a new clinical test for the detection of well‐characterized genomic disorders caused by chromosomal deletions and duplications that result in gene copy number variation (CNV). This powerful assay detects an abnormality in approximately 7–9% of patients with various clinical phenotypes, including mental retardation. We report here on the results found in a 6‐year‐old girl with mildly dysmorphic facies, obesity, and marked developmental delay. CMA was requested and showed a heterozygous loss in copy number with clones derived from the genomic region cytogenetically defined as Xq27.3–Xq28. This loss was not cytogenetically visible but was seen on FISH analysis with clones from the region. Further studies confirmed a loss of one copy each of the FMR1, FMR2, and IDS genes (which are mutated in Fragile X syndrome, FRAXE syndrome, and Hunter syndrome, respectively). Skewed X‐inactivation has been previously reported in girls with deletions in this region and can lead to a combined Fragile X/Hunter syndrome phenotype in affected females. X‐inactivation and iduronate 2‐sulfatase (IDS) enzyme activity were therefore examined. X‐inactivation was found to be random in the childs peripheral leukocytes, and IDS enzyme activity was approximately half of the normal value. This case demonstrates the utility of CMA both for detecting a submicroscopic chromosomal deletion and for suggesting further testing that could possibly lead to therapeutic options for patients with developmental delay.

Narrowing critical regions and determining penetrance for selected 18q- phenotypes.

One of our primary goals is to help families who have a child with an 18q deletion anticipate medical issues in order to optimize their childs medical care. To this end we have narrowed the critical regions for four phenotypic features and determined the penetrance for each of those phenotypes when the critical region for that feature is hemizygous. We completed molecular analysis using oligo‐array CGH and clinical assessments on 151 individuals with deletions of 18q and made genotype–phenotype correlations defining or narrowing critical regions. These nested regions, all within 18q22.3 to q23, were for kidney malformations, dysmyelination of the brain, growth hormone stimulation response failure, and aural atresia. The region for dysmyelination and growth hormone stimulation response failure were identical and was narrowed to 1.62 Mb, a region containing five known genes. The region for aural atresia was 2.3 Mb and includes an additional three genes. The region for kidney malformations was 3.21 Mb and includes an additional four genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the growth hormone stimulant response failure region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant. Identification of these critical regions suggest possible candidate genes, while penetrance calculations begin to create a predictive phenotypic description based on genotype.

Recurrent interstitial deletions of proximal 18q: A new syndrome involving expressive speech delay

Most deletions of the long arm of chromosome 18 involve some part of the most distal 30 Mb. We have identified five individuals with cytogenetically diagnosed interstitial deletions that are all proximal to this commonly deleted region. The extent of their deletions was characterized using molecular and molecular cytogenetic techniques. Each participant was assessed under the comprehensive clinical evaluation protocol of the Chromosome 18 Clinical Research Center. Three of the five individuals were found to have apparently identical interstitial deletions between positions of 37.5 and 42.5 Mb (18q12.3 → 18q21.1). One individuals deletion was much larger and extended from a more proximal breakpoint position of 23 Mb (18q11.2) to a more distal breakpoint at 43 Mb (18q21.1). The fifth individual had a proximal breakpoint identical to the other three, but a distal breakpoint at 43.5 Mb (18q21.1). The clinical findings were of interest because the three individuals with the smaller deletions lacked major anomalies. All five individuals were developmentally delayed; however, the discrepancy between their expressive and receptive language abilities was striking, with expressive language being much more severely affected. This leads us to hypothesize that there are genes in this region of chromosome 18 that are specific to the neural and motor planning domains necessary for speech. Additionally, this may represent a previously underappreciated syndrome since these children do not have the typical clinical abnormalities that would lead to a chromosome analysis.

correlates of biopsy-studied nephropathy in young patients with insulin-dependent diabetes mellitus

We have correlated pathologic findings in kidney biopsies from 12 adolescents with proteinuria or hypertension with severity of limited joint mobility (LJM) and retinopathy. We compared mean glucosylated hemoglobin (GHB) and clinical findings in these patients with those in patients without proteinuria or hypertension. Severity of LJM correlated with basement membrane thickening. Protein excretion correlated with degree of mesangial matrix increase and basement membrane changes. Retinal changes were related to basement membrane thickness and duplication. Despite treatment, blood pressures were significantly higher in patients with nephropathy than in the comparison group. Glycemic control status was generally poor and did not correlate with pathologic changes. The narrow spectrum of control did not permit assessment of possible effects of milder metabolic derangement. However, the similarity of GHB values in the groups with and without nephropathy implicates other factors. The group with clinical nephropathy had more LJM than did the comparison group, reaffirming LJM as a risk factor for early microvascular disease. Biopsy changes of nephropathy may begin relatively early in the course of diabetes (less than 7 years in three of our patients) and is already advanced when proteinuria appears.

Second 46,XX male with MLS syndrome

We report on a second 46,XX male with microphthalmia with linear skin defects (MLS) syndrome. In addition to microphthalmia and linear skin streaks, he had a secundum ASD, hypospadias with chordee, anal fistula, and agenesis of corpus callosum with colpocephaly. Biopsy of a linear streak showed smooth muscle hamartomata rather than the presumed dermal aplasia. Detailed ophthalmologic examination did not show retinal lacunae typical of Aicardi syndrome. DNA studies with distal Xp specific probes indicated a deletion in one X chromosome and fluorescence in situ hybridization (FISH) studies with X- and Y-specific probes demonstrated the presence of a derivative X chromosome from an X;Y translocation.