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Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and pigmentation deficiency of the hair, skin, and eyes. Klein‐Waardenburg syndrome (Waardenburg syndrome type 3) represents a distinct presentation of Waardenburg syndrome type 1 and includes musculoskeletal abnormalities in addition to dystopia canthorum hearing loss and pigmentary changes. Heterozygous or homozygous variants in the PAX3 gene cause Klein‐Waardenburg syndrome. Here we report on a new severely affected child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe), review the features of the syndrome, and propose a new classification. The designation of Waardenburg syndrome should be given only to patients with monoallelic pathogenic variants in PAX3 whether or not musculoskeletal abnormalities are present. Patients with biallelic PAX3 variants should be outlined as a distinct group and designated Klein syndrome. [ABSTRACT FROM AUTHOR]

ABSTRACT Hemoglobin City of Hope (Hb‐COH), NC_000011.9(NM_000518.5):c.208G > A; NP_000509.1:p.(Gly70Ser), has rarely been described. The presentation ranges from asymptomatic heterozygosity to significant anemia in patients carrying an additional pathogenic variant in β‐globin. To elucidate the clinical spectrum of Hb‐COH, we analyzed 31 individuals carrying the variant, including, for the first time, homozygous individuals. Seven patients who were compound heterozygous for Hb‐COH and an additional variant in β‐globin, presented with mild‐to‐severe microcytic anemia and elevated hemoglobin‐A2. Three (43%) of these also had elevated fetal hemoglobin, but none required blood transfusions. Seven patients coinherited Hb‐COH with an ‐α3.7‐deletion (NG_000006.1:g.34247_38050del), their presentation ranged from mild microcytic anemia to normal blood counts. Three homozygous and 14 heterozygous individuals for Hb‐COH had normal blood counts. Most Hb‐COH alleles whose origin was traceable were from Ashkenazi Jews (70.4%). To conclude, while isolated Hb‐COH appears asymptomatic even in the homozygous state, it may cause significant anemia when coinherited with an additional pathogenic variant in β‐globin. Understanding the full impact of Hb‐COH is crucial for optimal patient management and for genetic counseling. [ABSTRACT FROM AUTHOR]

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium‐specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue‐specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi‐allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson‐Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base‐pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out‐of‐frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss‐of‐function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson‐Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns. [ABSTRACT FROM AUTHOR]