NEXT GENERATION GENETICS
IN THE N.I.C.U.
Melissa C Byler, MS, CGC
Joan E Pellegrino, MD, FACMG
and Robert Roger Lebel, MD, FACMG
Section of Medical Genetics
Department of Pediatrics
SUNY Upstate Medical University
9/16/2016
We have no conflicts of interest
CHROMOSOME ANALYSIS
1950s discovery era
1960s identify number and major changes
1970s banding at about 500 pixel level
1990s BAC probes about 5000 pixels
2000s oligonucleotides up to 135,000 pixels
2010s single nucleotide polymorphism (SNP)
arrays at 2.6 million pixels
Whole exome sequencing: 30 million bases
Farwell Gonzales KD, Li X, Lu HM, Lu H, Pellegrino JE,
Miller RT, Zeng W, Chao EC
SUNY Upstate Medical Univ, Div Development, Behavior
and Genetics , Dept Pediatrics
Diagnostic exome sequencing and tailored
bioinformatics of the parents of a deceased child
with Cobalamin deficiency suggests digenic
inheritance of the MTR and LMBRD1 genes
JIMD Rep 2015; 15: 29-37
2.5 month-old Patient presents with
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Episodes of apnea
Seizures
Cerebral atrophy (MRI)
Encephalopathy (EEG)
High blood Homocysteine
Low blood Methionine
Low vitamin B12
Methylmalonic aciduria
Homocystinuria
No megaloblastic anemia
MTR+ MTR+
LMBRD1+ LMBRD1-
MTR+ MTR+
LMBRD1+ LMBRD1-
MTR+ MTRLMBRD1+ LMBRD1+
MTR+ MTRLMBRD1+ LMBRD1-
MAGEL2 clinical history
NICU consult for dysmorphic features
–  Talipes Equinovarus
–  Hypoplastic male genitalia
–  Sacral dimple
–  Clenched hands
–  Hypotonia, poor suck
Normal male chromosomes, normal FISH 15q11
Complicated clinical course involving extended
NICU stay
WES undertaken
A
B
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Father
Mother
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C
Proband
MAGEL2 c.
3122DELT
(p.V1041AFS*7)
Figure 1: Pedigree and MAGEL2 c.3122DELT (p.V1041AFS*7)
mutation
(A) Familial pedigree. Shaded shapes indicate affected individuals.
Asterisk (*) indicates whole exome sequencing performed. (B) An
electropherogram of the c.3122DELT (p.V1041AFS*7) alteration in the
proband. (C) Sequence conservation plots at the mutated site amino acid
position across different species.
MAGEL2
Proband
Mother
Father
MAGEL2 clinical pictures
RYR1 clinical history
Female DOL6 with respiratory depression and
general hypotonia
EEG: bilateral cerebral dysfunction
MRI: possible cerebral atrophy
Limited joint extension hips, knees, and fingers
WES undertaken
Parents decide to discontinue support and she
expires on DOL 17
Homozygous RYR1 mutation
RYR1 laboratory findings
RYR1
Hypoplastic gray matter
Hypoplastic white matter
Global brain dysplasia
FINIS
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Thanks
Danke
Merci
Grazie
Gracias
Xie xie
Arigatou
Specibo
Asante
Toda
Mamnuun
Danyavad
Hvala
Gamsa-habnida