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DEVELOPMENTAL ABNORMALITIES OF THE BRAIN COMMON IN PHELAN-MCDERMID SYNDROME

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  2. DEVELOPMENTAL ABNORMALITIES OF THE BRAIN COMMON IN PHELAN-MCDERMID SYNDROME

Developmental abnormalities of the posterior fossa and cerebellum are a common feature of 22q13.3 deletion, Aldinger et al (p. 131, 10.1002/ajmg.a.35700) suggest.

Deletion of 22q13.3 causes Phelan-McDermid syndrome (PDS), which involves developmental delay and severe delay or absence of expressive speech. PDS is a contiguous gene deletion syndrome that includes SHANK3.

After brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH) in two patients with hemizygous chromosome 22q13.3 telomeric deletion, researchers aimed to determine whether developmental abnormalities of the cerebellum are consistent with 22q13.3 deletion syndrome. They examined brain imaging studies for 10 unrelated subjects with 22q13.3 terminal deletion.

In seven cases where availability of DNA and array technology allowed, the researchers mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism microarrays. They derived approximate deletion boundaries for three additional cases from clinical or published molecular data.

The researchers also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. The gene encodes a scaffolding protein that localizes to the postsynaptic density of excitatory synapses, is strongly expressed in the cerebral cortex and cerebellum, and has been proposed as the major cause for both the neurological features of the 22q13.3 deletion syndrome and for a monogenic form of autism. But the researchers' data from the single patient suggest that SHANK3 disruption is not sufficient to produce CBVH, though they suggest examination of additional patients.

They propose MCM-CBVH observed in the Phelan-McDermid syndrome is likely due to contributions from two or more genes in the region, possibly including PLXNB2 and MAPK8IP2.

FAMILIES IN INDIA AND WESTERN COUNTRIES DIFFER IN THEIR VIEWS ON GENETIC TESTING FOR INHERITED HEARING LOSS

Nahar et al (p. 76, DOI 10.1002/ajmg.a.35692) provide insight into attitudes toward genetic testing and prenatal diagnosis for hearing loss among affected Indian families.

Similar surveys have been carried out in Western countries, but little research has been done in developing countries to examine prevailing attitudes about genetic testing and prenatal diagnosis for deafness.

The researchers evaluated members of 28 Indian families affected by inherited hearing loss that included 23 hearing parents with a deaf child, four couples in which both partners are deaf, one deaf parent, and one deaf child.

In all, 26 (93%) families expressed interest in prenatal diagnosis, 22 (85%) hoped to avoid having another child with deafness, and four (15%) felt the test would help them prepare for a child with a hearing disability. Two families (7%) were not interested in prenatal diagnosis.

These responses contrast with attitudes prevalent in developed countries, where comparatively fewer parents want prenatal diagnosis for hearing loss, and most parents interested in testing wish to prepare themselves for a hearing-impaired child, the researchers say.

X-CHROMOSOME ARRAY USEFUL TO CONFIRM SUSPECTED X-LINKED CONDITIONS

X-chromosome array frequently detects genomic alterations and offers advantages when evaluating some specific X-linked conditions, but the test requires careful interpretation and correlation with clinical findings, write Zarate et al (p. 120, DOI: 10.1002/ajmg.a.35698).

While previous studies have limited the use of specific X-chromosome array to evaluate patients with intellectual disability, the researchers' retrospective analysis reviewed the utility of an X-chromosome array in a variety of clinical scenarios.

They divided 25 patients into four groups, according to the indication for the test. These included patients with autism spectrum disorders, developmental delay, and those with intellectual disability (ASDs/DD/ID) and known family history of neurocognitive disorders; ASDs/DD/ID without known family history of neurocognitive disorders; breakpoint definition of an abnormality detected by a different cytogenetic test; and evaluation of suspected or known X-linked conditions.

The researchers ordered a total of 59 studies and detected 27 copy number variants in 42% of patients. Findings were deemed pathogenic or likely pathogenic (27%), benign (7%), or uncertain (12%).

When the X-chromosome array was used to confirm a suspected X-linked condition, the test had a yield of 63% and was useful in evaluating and assessing risk in patients and families. Additionally, determining the significance of the findings from arrays requires careful interpretation and correlation, the researchers write.

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Figure 1A. Patient 23 at 4 years of age (14 kb duplication at Xq28 that included SLC6A8). Dysmorphic features included telecanthus, epicanthal folds, anteverted nares, and mild retrognathia. B. Patient 25 at 10 years of age (2 kb duplication at Xq24 with CUL4B included). Note the synophrys, long eyelashes, epicanthal folds, and downturned corners of the mouth.