John B. Moeschler

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10−5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support 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 indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

Evaluation of mental retardation: Recommendations of a consensus conference

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies

Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8–16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS—i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.

Clinical Genetic Evaluation of the Child With Mental Retardation or Developmental Delays

This clinical report describes the clinical genetic evaluation of the child with developmental delays or mental retardation. The purpose of this report is to describe the optimal clinical genetics diagnostic evaluation to assist pediatricians in providing a medical home for children with developmental delays or mental retardation and their families. The literature supports the benefit of expert clinical judgment by a consulting clinical geneticist in the diagnostic evaluation. However, it is recognized that local factors may preclude this particular option. No single approach to the diagnostic process is supported by the literature. This report addresses the diagnostic importance of clinical history, 3-generation family history, dysmorphologic examination, neurologic examination, chromosome analysis (≥650 bands), fragile X molecular genetic testing, fluorescence in situ hybridization studies for subtelomere chromosome rearrangements, molecular genetic testing for typical and atypical presentations of known syndromes, computed tomography and/or magnetic resonance brain imaging, and targeted studies for metabolic disorders.

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor–associated protein in the Mediator complex.

Comprehensive Evaluation of the Child With Intellectual Disability or Global Developmental Delays

Global developmental delay and intellectual disability are relatively common pediatric conditions. This report describes the recommended clinical genetics diagnostic approach. The report is based on a review of published reports, most consisting of medium to large case series of diagnostic tests used, and the proportion of those that led to a diagnosis in such patients. Chromosome microarray is designated as a first-line test and replaces the standard karyotype and fluorescent in situ hybridization subtelomere tests for the child with intellectual disability of unknown etiology. Fragile X testing remains an important first-line test. The importance of considering testing for inborn errors of metabolism in this population is supported by a recent systematic review of the literature and several case series recently published. The role of brain MRI remains important in certain patients. There is also a discussion of the emerging literature on the use of whole-exome sequencing as a diagnostic test in this population. Finally, the importance of intentional comanagement among families, the medical home, and the clinical genetics specialty clinic is discussed.

Evaluation of the Newborn With Developmental Anomalies of the External Genitalia

The newborn with abnormal genital development presents a difficult diagnostic and treatment challenge for the primary care pediatrician. It is important that a definitive diagnosis be determined as quickly as possible so that an appropriate treatment plan can be established to minimize medical, psychological, and social complications. The purpose of this review is to identify which newborns among those with abnormal genital development need to be screened for intersexuality, to outline the investigations necessary, and to suggest indications for referral to a center with experience in the diagnosis and management of these disorders. An outline is also presented of the embryology of the external genitalia indicating where errors can arise to provide a framework for pediatricians to use when counseling families. Although the focus of this review is on newborns with what has been termed “ambiguous genitalia,” it should be recognized that most genital abnormalities in newborns do not result in an ambiguous appearance. These anomalies include hypospadias, in which the genitalia are clearly malformed, although the sex is unquestionably male.

Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay.

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.

Neuroimaging findings in macrocephaly–capillary malformation: A longitudinal study of 17 patients

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly–Capillary Malformation (M–CM). This syndrome has been traditionally known as Macrocephaly–Cutis Marmorata Telangiectatica Congenita (M–CMTC), but we explain why M–CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2‐weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow–Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M–CM.

Genetic Evaluation of Intellectual Disabilities

All children with an intellectual disability (mental retardation) or global developmental delay should have a comprehensive evaluation to establish the etiology of the disability. A specific etiologic diagnosis offers the opportunity to discuss treatment, prognosis, and genetic recurrence risk. A diagnosis also avoids unnecessary testing and can lead to opportunities for improved health and functional outcomes. The key elements of the diagnostic evaluation are the medical and developmental history, 3-generation family history, dysmorphologic examination, neurologic examination, and judicious use of the laboratory and neuroimaging. All published guidelines for the evaluation of children with intellectual disability acknowledge that there is a substantial percentage of patients who are undiagnosed after a comprehensive evaluation and who deserve ongoing follow-up for the purpose of establishing a diagnosis. Recently, studies of the clinical application of array comparative genomic hybridization (aCGH) to individuals with intellectual disability indicate that this approach provides a diagnosis in as much as 10% of patients and that this technique is replacing the use of fluorescent in situ hybridization for subtelomere imbalances now used for such patients when the standard karyotype is normal. The literature suggests that history and examination by an expert clinician will lead to a diagnosis in 2 of 3 patients in whom a diagnosis is made. Laboratory studies alone, including neuroimaging, provide a diagnosis in the remaining one third. The approach to the evaluation of the patient in whom an etiologic diagnosis is not suspected after the history and physical examinations includes a standard karyotype, Fragile X molecular genetic testing, aCGH, and neuroimaging, based on the evidence to date. One can expect rapid changes in the microarray technology in the near future.