Benno Röthlisberger

Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel–Giedion syndrome

Background Mutations of the SET binding protein 1 gene (SETBP1) on 18q12.3 have recently been reported to cause Schinzel–Giedion syndrome (SGS). As rare 18q interstitial deletions affecting multiple genes including SETBP1 correlate with a milder phenotype, including minor physical anomalies and developmental and expressive speech delay, mutations in SETBP1 are thought to result in a gain-of-function or a dominant-negative effect. However, the consequence of the SETBP1 loss-of-function has not yet been well described. Methods Microarray-based comparative genomic hybridisation (aCGH) analyses were performed to identify genetic causes for developmental and expressive speech delay in two patients. SETBP1 expression in fibroblasts obtained from one of the patients was analysed by real-time RT-PCR and western blotting. A cohort study to identify nucleotide changes in SETBP1 was performed in 142 Japanese patients with developmental delay. Results aCGH analyses identified submicroscopic deletions of less than 1 Mb exclusively containing SETBP1. Both patients show global developmental, expressive language delay and minor facial anomalies. Decreased expression of SETBP1 was identified in the patients skin fibroblasts. No pathogenic mutation of SETBP1 was identified in the cohort study. Conclusion SETBP1 expression was reduced in a patient with SETBP1 haploinsufficiency, indicating that the SETBP1 deletion phenotype is allele dose sensitive. In correlation with the exclusive deletion of SETBP1, this study delimits a milder phenotype distinct from SGS overlapping with the previously described phenotype of del(18)(q12.2q21.1) syndrome including global developmental, expressive language delay and distinctive facial features. These findings support the hypothesis that mutations in SETBP1 causing SGS may have a gain-of-function or a dominant-negative effect, whereas haploinsufficiency or loss-of-function mutations in SETBP1 cause a milder phenotype.

Supernumerary marker chromosome (1) of paternal origin and maternal uniparental disomy 1 in a developmentally delayed child

Editor—At least 168 cases with a supernumerary marker chromosome (SMC) from all chromosomes not including chromosome 15 have been documented.1 Birth prevalence is estimated at 0.14 to 0.72 per 1000.2 Subjects with a SMC have a partial trisomy (duplication) and in some cases a partial tetrasomy (triplication) of the genetic material contained in the SMC. The risk of an abnormal phenotype associated with a randomly ascertained de novo SMC derived from acrocentric autosomes (excluding chromosome 15) is estimated to be approximately 7% compared with approximately 28% for SMCs derived from non-acrocentric autosomes.1 The great variability of clinical findings in patients with SMCs originating from the same chromosome is probably the result of variation in size and genetic content, the degree of mosaicism, and uniparental disomy of the normal homologues of the chromosome from which the SMC derived. Evidence that subjects with SMCs might have an increased risk for UPD of the structurally normal homologues of the SMCs has been reported by several authors. To the best of our knowledge the coexistence of SMCs with UPD has been described for chromosomes 6, 7, 15, 20, and X.3-7 Here, we describe a further patient with multiple congenital anomalies, developmental delay, and the unique finding of coexistence of SMC 1 mosaicism and maternal uniparental disomy 1. The female patient was born at term after an uneventful pregnancy. At her birth, her mother was 33 years old and her father was 47 years old. Birth weight was 2500 g and length 49 cm. At the age of 6 years, she was investigated because of mental retardation. Height (1.14 m) and weight (17 kg) were within the normal range, but head circumference (44 cm) was far below the 3rd centile. Additional findings were temporal narrowing, downward slanting palpebral fissures, …

Homozygous nonsense mutation in WNT10B and sporadic split-hand/foot malformation (SHFM) with autosomal recessive inheritance.

Split‐hand/foot malformation (SHFM) is a limb malformation affecting the central rays of the hands and/or feet. Isolated SHFM occurs within families but more often sporadically. Since most families with more than one patient show dominant inheritance with reduced penetrance, sporadic SHFM is generally considered to be due to dominantly inherited new mutations. Recently, recessive inheritance of SHFM was proposed in a highly consanguineous family with a homozygous missense mutation in WNT10B. Nevertheless, the assumption of a second locus was necessary to explain the observed phenotypes in this family. To date, no other family and no case of sporadic SHFM with WNT10B mutations are known. By examining WNT10B in a patient with sporadic SHFM, we identified a homozygous 4‐bp duplication resulting in a premature termination codon. Nine heterozygous relatives show no sign of SHFM. These findings have profound implications for genetic counseling. Obviously, sporadic SHFM may show recessive rather than dominant inheritance resulting in a 25% recurrence risk for sibs instead of a very low‐recurrence risk as generally presumed. Likewise, there is a very low‐recurrence risk for offspring of patients (unless there is consanguinity) instead of an estimated risk between 30% and 50%. It can be concluded that sporadic SHFM is not always a dominant trait. To determine the recurrence risk, patients affected with sporadic SHFM should be tested for mutations in WNT10B.

Interstitial deletion 1q42 in a patient with agenesis of corpus callosum : Phenotype-genotype comparison to the 1q41q42 microdeletion suggests a contiguous 1q4 syndrome

Interstitial deletions of 1q4 are rare and present with different deletion breakpoints and variable phenotype. We report on the clinical and molecular cytogenetic findings in a girl with minor anomalies, midline defects including prenatally ascertained agenesis of the corpus callosum, epilepsy and developmental delay. A de novo 5.45 Mb deletion almost exclusively located within 1q42 was found to cause this phenotype, which shows significant overlap with the microdeletion 1q41q42 syndrome reported in a few patients except for the agenesis of the corpus callosum. However, deletions in patients with the 1q41q42 syndrome mainly extend into the 1q41 region with a region of overlap including the DISP1 gene involved in the SHH pathway, which is not part of the 1q42 deletion in our patient. We suggest that an interaction of genes involved in pathways of embryonic development rather than haploinsufficiency of single genes in the so‐called critical regions is causing complex malformation syndromes due to cytogenetic microaberrations in the 1q4 region.

Deletion of 7q11.21‐q11.23 and infantile spasms without deletion of MAGI2

We report on the clinical and cytogenetic findings and on the array‐based characterization of an interstitial 7q11.21‐q11.23 deletion initially recognized by standard karyotyping in a 15‐month‐old female patient. Beginning at the age of 3 months and 2 weeks the patient had severe infantile spasms. Recently, it was reported that infantile spasms are associated with deletion of the MAGI2 gene on chromosome 7q11.23. Nevertheless, not all patients reported with deletions of MAGI2 developed infantile spasms and at least one reported patient with a deletion 7q11.23 without missing the MAGI2 gene was diagnosed with infantile spasms. Molecular karyotyping of our patient confirmed a large 13 Mb deletion encompassing the 7q11.21‐q11.23 region without involvement of MAGI2. Critical review of published data and the results of our patient underline the importance to map precisely the deletion boundaries of further patients to reevaluate the significance of MAGI2 hemizygosity in the pathogenesis of infantile spasms.

Severe intra-uterine growth retardation in a patient with maternal uniparental disomy 22 and a 22-trisomic placenta.

We report on a maternal uniparental disomy of chromosome 22 in a patient with severe intra‐uterine growth retardation. Karyotyping of a placental tissue revealed non‐mosaic trisomy 22, whereas lymphocyte chromosomes from the newborn were normal 46,XY. Microsatellite analysis using DNA extracted from white blood cells showed maternal uniparental heterodisomy for chromosome 22. Thus, the conceptus started as maternal trisomy due to meiotic non‐disjunction, and trisomy rescue occurred subsequently through loss of the paternal homologue resulting in maternal uniparental disomy. Normal phenotypes in previous reports have suggested that maternal UPD 22 has no impact on the phenotype. Thus, growth retardation in this patient was probably caused by dysfunction of the trisomic placenta. Copyright

Essentially pure partial trisomy (6)(p23-->pter) in two brothers due to maternal t(6;17)(p23;p13.3).

We report on two brothers with low birth weight, growth retardation, microcephaly, minor facial anomalies, mental retardation, and trisomy (6)(p23-->pter) due to a maternal t(6;17)(p23;p13.3). As demonstrated by fluorescent in situ hybridisation (FISH) with the Miller-Dieker cosmid probe (D17S379) and with a subtelomeric probe (D17S34) the additional deletion on 17p13 is very small, and therefore, the phenotype of these two boys is most likely the result of essentially pure partial trisomy 6p. Comparison of the clinical findings with those of ten cases from the literature of dup(6p) with a breakpoint in or more distal to 6p23 allows delineation of a specific phenotype of dup(6)(p23-->pter) characterized by low birth weight, growth retardation, microcephaly, and blepharophimosis, blepharoptosis, microstomia, and abnormal ears.

Recurrence risk in de novo structural chromosomal rearrangements

According to the textbook of Gardner and Sutherland [ 2004 ], the standard on genetic counseling for chromosome abnormalities, the recurrence risk of de novo structural or combined structural and numeric chromosome rearrangements is less than 0.5–2% and takes into account recurrence by chance, gonadal mosaicism, and somatic‐gonadal mosaicism. However, these figures are roughly estimated and neither any systematic study nor exact or evidence‐based risk calculations are available. To address this question, an extensive literature search was performed and surprisingly only 29 case reports of recurrence of de novo structural or combined structural and numeric chromosomal rearrangements were found. Thirteen of them were with a trisomy 21 due to an i(21q) replacing one normal chromosome 21. In eight of them low‐level mosaicism in one of the parents was found either in fibroblasts or in blood or in both. As a consequence of the low number of cases and theoretical considerations (clinical consequences, mechanisms of formation, etc.), the recurrence risk should be reduced to less than 1% for a de novo i(21q) and to even less than 0.3% for all other de novo structural or combined structural and numeric chromosomal rearrangements. As the latter is lower than the commonly accepted risk of approximately 0.3% for indicating an invasive prenatal diagnosis and as the risk of abortion of a healthy fetus after chorionic villous sampling or amniocentesis is higher than approximately 0.5%, invasive prenatal investigation in most cases is not indicated and should only be performed if explicitly asked by the parents subsequent to appropriate genetic counseling.

Familial 14.5 Mb interstitial deletion 13q21.1-13q21.33: clinical and array-CGH study of a benign phenotype in a three-generation family.

We report on the clinical and cytogenetic findings as well as the array‐based characterization of an interstitial familial 13q21 deletion initially recognized by standard karyotyping. Although 13q deletions are known to imply a wide variability of clinical consequences, the deletion carriers of the familial deletion in three generations did not reveal a relevant phenotype. The breakpoints and the deletion size in all three carrier individuals were determined by molecular karyotyping confirming a large 14.5 Mb deletion encompassing the 13q21.1–13q21.33 region identical in all three carriers. Gene paucity and the lack of dosage‐sensitive genes in the delineated region might explain the apparently innocuous nature of this chromosomal anomaly. The example of this family presents evidence for describing the chromosomal region 13q21.1–13q21.33 as a large euchromatic variant or benign copy number variation without phenotypic consequences. Our data underline the importance of a phenogenetic approach combining clinical and laboratory evidence in the interpretation of segmental chromosomal anomalies especially in genetic counseling related to prenatal diagnosis.

PK Aarau: first homozygous nonsense mutation causing pyruvate kinase deficiency

The study was supported by Cofin 2002, MIUR, Rome, Italy; Progetto Strategico Oncologia, CNR-MIUR, Rome, Italy; Ricerca Finalizzata 2002, Ministero della Salute, Rome, Italy; Regione Piemonte, Torino, Italy; and Novara-AIL Onlus, Novara, Italy. EB is supported by a fellowship from Fondazione ‘Piera Pietro e Giovanni Ferrero, Alba, Italy. LP is a Special Fellow of the Leukemia and Lymphoma Society.