Mendels laws, like any laws in science, are wonderful because they make predictions possible. A woman and man both carry a recessive mutation in the same gene, and each of their children has a 25% chance of inheriting both mutations and the associated health condition. Bio 101.

In contrast to our bizarre new world of alternate facts, multiple interpretations, and both are true scenarios, science is both logical and rational. If an observation seems to counter dogma, then we investigate and get to the truth. Thats what happened for Millie and Hannah, whose stories illustrate two ways that genetic disease can seem to veer from the predictions of Mendels first law: that genes segregate, one copy from each parent into sperm and ova, and reunite at fertilization. (Ill get to embryo engineering at the end.)

Millies situation is increasingly common exome or genome sequencing of a child-parent trio reveals a new (de novo), dominant mutation in the child, causing a disease that is genetic but not inherited.

Hannahs situation is much rarer: inheriting a double dose of a mutation from one parent and no copies of the gene from the other.

MILLIE AND BAINBRIDGE-ROPERS SYNDROME

Millie McWilliams was born on September 2, 2005. At first she seemed healthy, lifting her head and rolling over when most babies do. But around 6 months, her head became shaky, like an infants. Then she stopped saying dada, recalled her mother Angela.

By Millies first birthday, her head shaking had become a strange, constant swaying. She couldnt crawl nor sit, had bouts of irritability and vomiting, and bit her hands and fingers.

In genetic diseases, odd habits and certain facial features can be clues, but none of the many tests, scans, and biopsies that Millie underwent lead to a diagnosis. Nor were her parents carriers of any known conditions that might explain her symptoms. Still, it was possible that Millie had an atypical presentation of a recessive condition so rare that it isnt included in test panels.

By age 6 Millie couldnt speak, was intellectually disabled, and was confined to a wheelchair, able to crawl only a few feet. Today she requires intensive home-based therapies. But Millie can communicate. She likes to look at what she wants, with an intense stare, said Angela. She loves country music and Beyonc, and every once in awhile something funny will happen and shell break into a big smile.

Millies pediatrician, Dr. Sarah Soden, suggested that trio genome sequencing, just beginning to be done at Childrens Mercy Kansas City(where the child already received care) as part of a long-term project, might help to assemble the clinical puzzle pieces to explain the worsening symptoms. So the little girl and her parents, Angela and Earl, had their genomes sequenced in December 2011. Analyzing the data took months, but Dr. Sodens team finally found a candidate mutation in the child but not her parents. However the gene, ASXL3, hadnt been linked to a childhood disease. Yet.

Its typically a matter of time for gene annotation to catch up to sequencing efforts and clinical clues. In February of 2013, a report in Genome Medicinedescribed four children with mutations in ASXL3 who had symptoms like Millies. Even her facial structures arched eyebrows, flared nostrils, and a high forehead matched those of the other children, as well as the hand-biting. They all haveBainbridge-Ropers syndrome.

One copy of Millies ASXL3 gene is missing two DNA bases, creating an inappropriate stop codon and shortening the encoded proteins. From this new glitch somehow arose the strange symptoms. Because neither Earl nor Angela has the mutation, it must have originated in either a sperm or an egg that went on to become Millie.

Since the paper about Bainbridge-Ropers syndrome was published three years ago, a few dozen individuals have been diagnosed and families have formed a support group and a Facebookpage. Thats huge. Even if a disease has no treatment, as is the case for Bainbridge-Ropers, families find comfort in reaching the end of the diagnostic odyssey and locating others. Said Angela, It was a relief to finally put a name on it and figure out what was actually going on with her, and then to understand that other families have this too. Ive been able to read about her diagnosis and what other kids are going through.

HANNAH AND GAN

Hannah Sames will be celebrating her 13th birthday next month, and is showing what may be early signs of strength in her muscles after receiving gene therapyinto her spinal cord last summer to treat giant axonal neuropathy (GAN).

When I first met Hannahs mom Lori in 2010, she told me that Hannah had inherited the exact same deletion mutation in the gigaxonin gene from her and her husband Matt. At that time, only a few dozen children were known to have the condition, and that number hasnt risen much. Because of the diseases rarity, I politely asked ifLori and Matt could be cousins but not know it. Shared ancestry seemed a more likely explanation for two identicalextremely rare gene variants occurring in the same child than the parents having the same length deletion just by chance. But no, Matt and Lori arent related.

The answer came just a few months ago: Hannah inherited both of her gigaxonin deletion mutations from Lori, and none from Matt. This is a very rare phenomenon called uniparental disomy (UPD), meaning two bodies from one parent. Like Millie, UPD seemingly defies Mendels law of segregation, with a pair of chromosomes (or their parts) coming solely from one parent, rather than one from each parent.

UPD happens during meiosis, the form of cell division that sculpts egg and sperm. And it requires two exceedingly rare events.

First, something goes wrong during the separation of one chromosome in which the DNA has replicated to form two chromatids, like two squiggly lines of DNA linked at the middle. Instead of those chromatids separating into different eggs, a pair went into the same egg, providing two copies of the chromosome 16 that bears the mutation, instead of the normal one. For a child with GAN to have resulted from Loris meiotic glitch, her double-dose egg must have met with a sperm cell that just happened to be missing chromosome 16 thats the second rare event. Or, more likely, the one-celled Hannah indeed had a chromosome 16 from her dad yet had two from her mom, an anomaly in chromosome assortment called nondisjunction. In fact an extra chromosome 16 is the most common trisomy(3 instead of 2 chromosomes) associated with miscarriage. But then Matts chromosome was lost, leaving two from Lori.

Neither Millies Bainbridge-Ropers syndrome nor Hannahs GAN actually counters Mendels law. Although Millie didnt inherit her mutation, if she were able to have children, she would pass it on with a probability of 1 in 2 to each child, just like the law predicts for dominant inheritance. Likewise, a child of Hannah would inherit one copy of the mutation that causes GAN when present in a double dose, just like the law predicts for recessive inheritance.

FORGET EDITING THE GERMLINE GENOME AND HELP SICK KIDS

As I was writing this post, the National Academy of Sciencesreleased its long-awaited tome on whats being called, among other things, embryonic engineering. Rather than banning editing of the human germline forever, the report foresees certain situations in which gene or genome editing, using CRISPR-Cas9 or some other variation on the theme, might be deployed to prevent disease.

WhileI think its great that the rare scenarios in which genome editing might be useful are finally being spelled out, instead of flaming fears of genetic enhancement spawning designer babies, my thinking aboutMillie and Hannah made me wonder why we would ever need to edit a genome to prevent disease in the first place. To quote the eminent mathematician from Jurassic Park, Ian Malcolm, Yeah, yeah, but your scientists were so preoccupied with whether or not they could that they didnt stop to think if they should.

Preventing illness in a future child of course isnt the same as designing theme park dinosaurs, but like Jurassic Parks technology, I cant imagine why genome editing at very early developmental stages is necessary.Even for an exceedingly rare family situation in which passing on an inherited disease is unavoidable, according to Mendels laws, there are alternatives, although they do not yield a biological child: replace, select, or adopt:

Instead of replacing errant genes early in prenatal development, or even before, I think we should focus instead on helping the Millies and Hannahs who are no longer fertilized ova or early embryos, but are kids. Thats already starting for Hannah, thanks to the gene therapy technology that has been gestating since 1990. Millies turn hasnt come yet.

So yes, lets set rules for editing the human germline but lets also consider whether this type of intervention will ever even be necessary in our overcrowded world.

See original here:
Defying Mendelian Genetics and Embryo Engineering - PLoS Blogs (blog)