The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

A diagnostic approach to identifying submicroscopic 7p21 deletions in Saethre-Chotzen syndrome: fluorescence in situ hybridization and dosage-sensitive Southern blot analysis.

PURPOSE: To report on the use of fluorescence in situ hybridization (FISH) and dosage-sensitive Southern blot analysis in the molecular diagnosis of patients with Saethre-Chotzen syndrome. METHODS: FISH and dosage-sensitive Southern blot analysis utilizing TWIST gene probes were performed on patients with Saethre-Chotzen syndrome but without an identifiable TWIST sequence variation. RESULTS: Four unrelated patients with a deletion of the TWIST gene were identified by Southern blot; one of them had a complex chromosomal rearrangement involving 7p21 and no apparent deletion by FISH, suggesting a smaller deletion in the region including the TWIST gene. A fifth patient had an abnormal TWIST gene fragment on Southern blot analysis that segregated with the disease in the family; FISH was normal in this patient, suggesting a partial deletion or rearrangement in or near the gene. CONCLUSION: FISH and dosage-sensitive Southern blot analysis are useful diagnostic tools in Saethre-Chotzen syndrome without TWIST sequence variation.

Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.

The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting. PWS becomes apparent when genes on the paternally inherited chromosome are not expressed. Familial PWS is rare. We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes. Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3. The cousins' fathers and two paternal aunts have the same deletion and are clinically normal. The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN. DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS. "Grandmatrilineal" inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line. This represents a unique inheritance pattern due to imprinting.

Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion.

A microscopic deletion of chromosome 22q11.2 has been identified in most patients with the DiGeorge, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies. This study presents the neurodevelopmental outcome, including cognitive development, language development, speech, neuromuscular development, and behavioral characteristics of 40 preschool children (ages 13 to 63 months) who have been diagnosed with the 22q11.2 deletion. The impact of cardiac disease, cardiac surgery, and the palatal anomalies on this population was also studied. In the preschool years, children with a 22q11.2 deletion are most commonly found to be developmentally delayed, have mild hypotonia, and language and speech delays. The more significantly delayed children are at high risk to be subsequently diagnosed with mild or moderate mental retardation. The global delays and the variations in intelligence found are directly associated with the 22q11.2 deletion and are not explained by physical anomalies such as palatal defects or cardiac defects, or therapeutic interventions such as cardiac surgery. Our findings demonstrate that there is a pattern of significant speech disorders within this population. All of the children had late onset of verbal speech. Behavioral outcomes included both inhibition and attention disorders. Early intervention services are strongly recommended beginning in infancy to address the delays in gross motor skills, speech and language, and global developmental delays.

Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Börjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome. We have identified a male patient with BFLS-like features and a duplication, 46,Y,dup(X)(q26q28), inherited from his phenotypically normal mother. Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an approximately 400-kb interval in the Xq26.3 region between DXS155 and DXS294/DXS730. Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval. The gene structure of FHF2 was determined and two new exons were identified, including a new 5' end exon, 1B. FHF2 is a large gene extending over approximately 200 kb in Xq26.3 and is composed of at least seven exons. It shows tissue-specific alternative splicing and alternative transcription starts. Northern blot hybridisation showed highest expression in brain and skeletal muscle. The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candidate gene for familial cases of the BFLS syndrome and other syndromal and non-specific forms of X-linked mental retardation mapping to the region.

De novo alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.

Apert syndrome, one of five craniosynostosis syndromes caused by allelic mutations of fibroblast growth-factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and feet. We have analyzed 260 unrelated patients, all but 2 of whom have missense mutations in exon 7, which affect a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. FGFR2 mutations in the remaining two patients are distinct in position and nature. Surprisingly, each patient harbors an Alu-element insertion of approximately 360 bp, in one case just upstream of exon 9 and in the other case within exon 9 itself. The insertions are likely to be pathological, because they have arisen de novo; in both cases this occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth-factor receptor [KGFR] and bacterially expressed kinase, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Splicing of exon 9 was examined in RNA extracted from fibroblasts and keratinocytes from one patient with an Alu insertion and two patients with Pfeiffer syndrome who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome.

Hemifacial microsomia in a newborn with hypoplastic skin lesions, an eyelid skin tag, and microphthalmia: an unusual presentation of Delleman syndrome.

Delleman syndrome (oculocerebrocutaneous syndrome) is characterized by orbital cysts, periorbital skin appendages, and focal cutaneous hypoplasia. We describe a male infant with findings associated with this condition, including an eyelid appendage, discrete hypoplastic skin lesions, unilateral microphthalmia, and hydrocephalus. In addition, he had striking unilateral mandibular hypoplasia and microtia, features often present in the oculoauriculovertebral (OAV) spectrum. However, hypoplastic skin lesions and eyelid appendages are not features of the OAV spectrum. The marked degree of hemifacial microsomia present in this child has not been previously noted in Delleman syndrome. Two patients with Delleman syndrome have been previously described who have features typically present in the OAV spectrum. This case demonstrates that characteristics of both Delleman syndrome and the OAV spectrum may be present in one individual.

Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.

We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.

Further clinical delineation and increased morbidity in males with osteopathia striata with cranial sclerosis: an X-linked disorder?

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by hypertelorism, macrocephaly, frontal bossing, broad nasal bridge, palate anomalies, hearing deficits, and mental retardation. The radiographic findings include cranial sclerosis, linear striations in the long bones and iliac wings, small poorly aerated sinuses, scoliosis, and increased bone density. The sensory deficits are disabling, but the condition generally is not life threatening. We describe 4 brothers with the characteristics of OS-CS, 3 of whom have died from more serious complications of the disorder. The mother of these children, and her only daughter, have the mildest phenotype with the typical linear striations in the long bones and macrocephaly. OS-CS is thought to be autosomal dominant with complete penetrance and variable expressivity. Our observations could be consistent with X-linkage, since there is milder expression in the female relatives. In addition, we recognize absent fibulae, malrotation, and omphalocele as new manifestations as well as congenital heart disease.

Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism?

Cleidocranial dysplasia (CCD) is classically an autosomal dominant disorder. However, the possibility of an autosomal recessive form of CCD has been suggested based on a report of 2 consanguineous families, one with a single affected child, the second with affected sibs, born to normal parents. We present a family with sibs with CCD born to normal parents, and suggest germ line mosaicism as the more likely mechanism for this occurrence.

Nasal dimple as part of the 22q11.2 deletion syndrome.

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia.

Heterotaxia in a fetus with campomelia, cervical lymphocele, polysplenia, and multicystic dysplastic kidneys: expanding the phenotype of Cumming syndrome.

We report on a fetus with tetramelic campomelia, polysplenia, multicystic dysplastic kidneys, and cervical lymphocele. This condition is similar to the autosomal recessive condition described by Cumming et al. [1986: Am J Med Genet 25:783-790] and is different from campomelic syndrome. In addition, our case had anomalies not previously described in this condition, including abnormal lung lobation with bilateral left bronchial morphology, dextrocardia, total anomalous pulmonary venous return, a left superior vena cava, and a right aortic arch. The pancreas was short, with absence of the body and tail. These anomalies are similar to those found in the polyasplenia spectrum. We suggest that the syndrome reported by Cumming et al. may be expanded to include polysplenia with heterotaxia and that Cumming syndrome may be considered another autosomal recessive condition associated with a laterality defect.

PCR assay confirms diagnosis in syndrome with variably expressed phenotype: mutation detection in Stickler syndrome.

Stickler syndrome is an autosomal dominant disease with ocular (severe myopia, vitreal degeneration, and retinal detachment) and other systemic manifestations (hearing loss, cleft palate, epiphyseal dysplasia, and premature osteoarthritis). As with other dominantly inherited conditions, the clinical phenotype of Stickler syndrome varies considerably. To date, all mutations have been located in the type II procollagen (COL2A1) gene. Analysis of a C-->T mutation we had identified previously, in COL2A1 gene in exon 40, in a three generation pedigree showed the loss of a cleavage site for the TaqI restriction enzyme. We designed a rapid PCR based restriction enzyme assay to detect this mutation and used it to establish the diagnosis in a neonate from the same pedigree, presenting with the first occurrence of the Pierre-Robin sequence in the family and minimal ocular findings. These results underline the potential diagnostic value of many as yet undetected DNA mutations in families affected with Stickler syndrome, since the variability of the phenotype can impede accurate diagnosis, appropriate genetic counselling, and effective intervention and prophylactic treatment for affected people.

Saethre-Chotzen syndrome with familial translocation at chromosome 7p22.

Chromosome analysis of a male infant and his mother with Saethre-Chotzen syndrome demonstrated an apparently balanced translocation, t(2;7)(p23;p22). This association lends support to localization of the gene for Saethre-Chotzen syndrome to the 7p2 region and supports further involvement of gene(s) in the 7p22 region.

On lumping and splitting: a fetus with clinical findings of the oral-facial-digital syndrome type VI, the hydrolethalus syndrome, and the Pallister-Hall syndrome.

The three midline malformation complexes, the oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome, the hydrolethalus syndrome (HS), and the Pallister-Hall syndrome (PHS) have been described as distinct genetic entities. Here, we report a fetus with a combination of clinical findings of all 3 syndromes similar to the twin fetuses described in the accompanying paper (Hingorani et al., 1991). The phenotypic overlap in these fetuses with the OFDS VI, HS, and PHS raises the question as to whether or not they indeed represent separate genetic entities as previously assumed.

Oculodentodigital dysplasia syndrome associated with abnormal cerebral white matter.

Oculodentodigital dysplasia (ODDD) syndrome is an uncommon inherited disorder with eye and facial abnormalities, syndactyly, and defects in tooth enamel. Some of the previously reported patients with ODDD syndrome also manifested spastic quadriparesis. We describe a patient with sporadic ODDD syndrome referred for evaluation of progressive spastic paraparesis. Magnetic resonance imaging of the brain demonstrated abnormal white matter, which suggests an explanation for the observed spastic paraparesis.

Interstitial deletion of 4(q21q25) in a liveborn male.

We describe a liveborn male with a de novo deletion of 4(q21q25). The findings in this infant are compared with those of other 4q interstitial deletion patients with similar break-points. Given the reproducible findings including skull asymmetry, cardiac defects, renal cysts, "butterfly" vertebrae, as well as a particular dysmorphic face with developmental delay, there is evidence for an interstitial 4q deletion syndrome.